A 10-Year Perspective on the Utility of Three Adjuvants Often Used in IVF: Growth Hormone, Melatonin and DHEA

Round 1

Reviewer 1 Report

This commentary is written to provide single center experience in the use of three adjuvants for IVF.  Thank you for providing this perspective on a topic that is important to all providers who treat patients with ART, as we all suffer from wishing there was more to offer our poor prognosis patients in many cases.  

I would suggest fleshing out the introduction slightly to include where the authors plan to take the reader on this journey, because it was not apparent from this short paragraph, and required piecing together on multiple reads to get the best clear picture.  For example, at least mentioning that you will focus on some research designed to improve outcomes for these poor prognosis patients you mention, which of course you reiterate later.

For the historical context section, I'm not sure how this fits into your story other than to establish the credentials of one of the authors, which may not serve the greater narrative as much as feel like a sidebar.  If you do retain mention of the ANZARD database in your final manuscript, you might point out how it fits into your larger narrative (e.g. this database helps us to know what typical success rates are so that we are able to identify that there is a gap that requires further research, etc...)

After these 2 sections the authors do lay out a good case for further research into poor prognosis patients and what can be done to help them.

In section 4, a significant portion of this is dedicated to touting the gonadotropin dosing protocol used at PIVET so I did not come away feeling that the header topic was actually the focus.  Consider putting into a separate section.

In section 5 you use different terminology in the header than you do in the paragraph, again making the reader work a little harder to reach your main takeaway point, which I believe is that you recommend a definition of "poor prognosis" to include certain characteristics and to focus on what can improve outcomes for this population.  And that you're presenting research that did classify patients this way and had the following findings... correct?

Other than counting the number of citations, it is hard to tell how many studies you are referencing throughout the paper.  This might be helpful for strength of evidence if it can flow into your narrative.

In section 7, you lay out your arguments for why your research should carry weight compared to other literature.  Mentioning your dosing algorithm and focusing on its benefits in high responders (reduced OHSS, less freeze-all) does seem like a variation away from the main focus of the group of patients that you argue would benefit from the adjuvants GH and DHEA.  It feels like a distraction from your main narrative.

I also found it somewhat confusing reading straight through that there are two different sections which present data and conclusions from your adjuvant studies, section 6 and section 9, and they are stated enough differently in the 2 places that I went back and forth comparing them.

The authors' point that more studies are needed with focus on specific groups most likely to benefit from adjuvant therapy is well taken, but the road to get there was slightly winding and would be more crystallized with some editing to focus again on these main points.

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

Thank you for giving me the opportunity to review the manuscript “A 10-year perspective on the utility of 3 adjuvants often used in IVF: growth hormone, melatonin and DHEA”, which I have read with great interest.

Poor ovarian response to gonadotropin stimulation is a major challenge for IVF clinicians. The manuscript summarizes the authors’ many years of experience on the use of three different adjuvants (growth hormone, dehydroepiandrosterone and melatonin) given to improve the ovarian response. Their analysis demonstrates interesting findings in terms of laboratory and clinical outcomes. A subgroup of poor responder women, particularly those who have poor embryo quality and additional poor prognostic factors, seem to benefit from growth hormone and DHEA supplementation, alone or in combination. The authors suggest that future prospective studies should target this specific patient population. Melatonin, on the other hand, does not provide any benefit.

The manuscript is clear, well-written and informative.  Presented data are interesting and they justify the conclusions. The references are mainly primary sources; they are complete and accurate.

The report clearly adds to the literature already available on the subject. I strongly recommend its publication.

My only contribution would be pointing out a few typos that I have noticed (please see the attached file).

Comments for author File: Comments.pdf

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

The authors present a critical review of their clinical experience with the use of three popular adjuvants in ovarian stimulation protocols: recombinant human growth hormone (rGH), dehydroepiandrosterone (DHEA) and melatonin. Data presented are confronted with those from other clinics and suggest an interest in using rGH in certain subgroups of patients, namely those of advanced age, very low ovarian reserve or recurrent implantation failure. Data for DHEA are inconclusive and need more studies to be refined, while melatonin does not appear to produce any significant benefit.

The subject of the study is topical, and the manuscript is well written. The conclusions drawn are clear, and the literature is complete.

I recommend the acceptance of the manuscript in its present form.

Author Response

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Author Response File: Author Response.docx