Pre-Conceptual Guidelines for Men: A Review of Male Infertility Experience, including Nutrition and Lifestyle Factors

Round 1

Reviewer 1 Report

Developing pre-conceptual guidelines for men: a review of male infertility experience, including nutrition and lifestyle factors 2000-2021

Abstract

Lines 10-13     Lengthy and awkwardly phrased sentence beginning Semen parameters can be improved ; suggest rephrase, condense to 2 sentences

Line 13-14       Explore ‘experience of infertility in males’ – experiences suggests personalized interviews, focus groups, narratives- rather than outcome based on preconception habits, factors.

Line 20-22       Rephrase to ensure clarity that dietary modifications/supplementation were the findings of the current systematic review and not more literature review/background… ditto Mediterranean style diet

Curious where the preconception emphasis on lifestyle and improving semen parameters will intersect with the emotional experience of infertility (Lines 23-25)

Introduction

Line 30- no need to capitalize Clinical Infertility

Line 40- rephrase ‘they must undergo’…. E.g. semen analysis, physical examination (and arguably hormone/blood test) are standard.

Line 42- do not capitalize Fragmentation

Line 61- spell out GP, NHS

Line 63-65 who provides this information? NHS? Citation please

Line 72-73- experience of infertility- relevant if you can show that the taboos/stigma make this audience more difficult to counsel regarding preconception interventions

Conclusion of Introduction overly weights Rossi- expand to include other sources and state aim.

Suggestions- could add that beyond acute fecundity, quality of sperm related to fetal outcomes- mentioned briefly with DNA fragmentation and miscarriage risk, but could go a bit further to DOHaD

Methodology

Interesting the inclusion of psychosocial impacts of male infertility- it would appear to be a bit outside the focused aim of the study. Please relate to the apparent aim of assessing nutritional/supplements in preconception guidelines. If aim is more broadly preconception guidelines, then the emphasis on non-nutrition factors is missing from the Introduction.

Please clarify inclusion/exclusion criteria. For example- ‘chemical’ would have yielded many papers, yet the review emphasizes classic environmental toxins such as BPA, phthalates and pesticides. Were no other chemicals such as medications or laboratory chemicals retrieved and subsequently excluded?

It would be helpful to see the findings structured as outcomes- generally most of the findings feature +/- impacts on sperm quality (volume, motility, concentration, morphology (DNA fragmentation), as well as hormone profiles. If these were the major outcome variables- please identify in the data analysis.

Findings

It would be helpful to identify major themes or findings for each topic- not currently apparent.

For each topic it would be helpful to see the papers charted in a table with parameters examined- eg. Study design, country of origin/setting/ major finding. Presumably some papers are represented in multiple topic areas.

The current presentation would seem to suggest that some topic areas- e.g. Dietary fats- included a single paper from the search strategy? Reference 49? Please confirm.

The findings do not explore possible confounding between body weight/BMI and various nutritional supplements/variables. For example- is reducing saturated fats or adhering to a Mediterranean style diet itself beneficial- or are these strategies that lower body weight/fat and therefore absence of obesity provides for normal endocrine profiles?

The preconception guidelines are nice to see, but several do not directly emerge from your current study (e.g. sleep habits, frequency of meals, chew food, STIs).

Overall- this paper does address an unmet gap in the field, however there are methodological/data presentation issues that should be improved prior to publication.

Author Response

Thank you for reviewing our paper.  

Abstract

Lines 10-13     Lengthy and awkwardly phrased sentence beginning Semen parameters can be improved ; suggest rephrase, condense to 2 sentences – agree - amended, split into two sentences

Line 13-14       Explore ‘experience of infertility in males’ – experiences suggests personalized interviews, focus groups, narratives- rather than outcome based on preconception habits, factors. Investigating experience to inform health professionals so more tailored nutritional recommendations can be developed. Have clarified.

Line 20-22       Rephrase to ensure clarity that dietary modifications/supplementation were the findings of the current systematic review and not more literature review/background… ditto Mediterranean style diet Have clarified

Curious where the preconception emphasis on lifestyle and improving semen parameters will intersect with the emotional experience of infertility (Lines 23-25) Have clarified  (lines 15-16) – it is to aid HCP to personalise recommendations and better support men experiencing infertility given the taboo.

Introduction

Line 30- no need to capitalize Clinical Infertility - amended

Line 40- rephrase ‘they must undergo’…. E.g. semen analysis, physical examination (and arguably hormone/blood test) are standard. Removed they must undergo 

Line 42- do not capitalize Fragmentation amended 

Line 61- spell out GP, NHS – amended

Line 63-65 who provides this information? NHS? Citation please This is from NICE CG156 (Reference 17) I have added the reference again to clarify the point

Line 72-73- experience of infertility- relevant if you can show that the taboos/stigma make this audience more difficult to counsel regarding preconception interventions clarified in abstract and added a few words to clarify  around what was line 72

Conclusion of Introduction overly weights Rossi- expand to include other sources and state aim. Aim has been added. Removed one mention of Rossi and added another source (26).

Suggestions- could add that beyond acute fecundity, quality of sperm related to fetal outcomes- mentioned briefly with DNA fragmentation and miscarriage risk, but could go a bit further to DOHaD Added.

Methodology

Interesting the inclusion of psychosocial impacts of male infertility- it would appear to be a bit outside the focused aim of the study. Please relate to the apparent aim of assessing nutritional/supplements in preconception guidelines. If aim is more broadly preconception guidelines, then the emphasis on non-nutrition factors is missing from the Introduction. We have now clarified in abstract and in introduction.

Please clarify inclusion/exclusion criteria. For example- ‘chemical’ would have yielded many papers, yet the review emphasizes classic environmental toxins such as BPA, phthalates and pesticides. Were no other chemicals such as medications or laboratory chemicals retrieved and subsequently excluded? Searches did not return a large number of results on this topic. It identified papers on pesticides, bisphenols pthalates which was possibly due to the narrow search terms for male fertility and the inclusion criteria of being male aged 19-64. Please see new table (table 3) and papers identified in sixth section environmental impacts – this will show the papers identified via our search.

It would be helpful to see the findings structured as outcomes- generally most of the findings feature +/- impacts on sperm quality (volume, motility, concentration, morphology (DNA fragmentation), as well as hormone profiles. If these were the major outcome variables- please identify in the data analysis. Added in to sections 4 a comment re different outcome variables. We have included a table (table 3) with the major findings of the studies reviewed

Findings

It would be helpful to identify major themes or findings for each topic- not currently apparent. We have included an extra paragraph on this and also detailed it in a new table (table 3).

For each topic it would be helpful to see the papers charted in a table with parameters examined- eg. Study design, country of origin/setting/ major finding. Presumably some papers are represented in multiple topic areas.  We undertook a narrative synthesis and reviewed papers grouped into 6 broad themes following analysis. Themes were general male fertility trends and sperm parameters, psycho-social impacts of male infertility, lifestyle impacts on male fertility, nutritional impacts on male fertility (food and drink), supplementation and male fertility and environmental impacts on male fertility. We have produced a table as additional information showing the papers falling under each category and country of study, main findings etc (table 3).

The current presentation would seem to suggest that some topic areas- e.g. Dietary fats- included a single paper from the search strategy? Reference 49? Please confirm. We used this paper as an introductory point to the section on fat highlight that fat is important for steroidogenesis, we have  proceeded to talk about other papers under sub headings considering types of fats - see 4.2.3 Trans fats are considered..4.2.4 Saturated fats are considered. 4.2.5 Polyunsaturated fats are considered.

The findings do not explore possible confounding between body weight/BMI and various nutritional supplements/variables. For example- is reducing saturated fats or adhering to a Mediterranean style diet itself beneficial- or are these strategies that lower body weight/fat and therefore absence of obesity provides for normal endocrine profiles? Have added a paragraph to the conclusion to cover this point, i.e. losing weight is beneficial in terms of endocrine profiles but data reviewed cannot say if it is just the effect of weight loss, given there are so many factors to consider and so many underlying processes or if it is the nutritional improvement and availability of antioxidants and reduction in ROS from dietary improvement or a combination.

The preconception guidelines are nice to see, but several do not directly emerge from your current study (e.g. sleep habits, frequency of meals, chew food, STIs). These are a part of accepted health advice and STI screening recommended in infertility, included for re-emphasis -  clarified within legend for table 3.

Overall- this paper does address an unmet gap in the field, however there are methodological/data presentation issues that should be improved prior to publication. Thank you for your comments and feedback on our paper. We have addressed your comments and those of the other reviewers so hope this have been addressed now.

Reviewer 2 Report

This Review is interesting, well organized and well written; its Sections are exhaustive, clearly developed and correctly synthetic. The presentation of the main concepts in Table 2 is excellent. I think that, if the Authors in Section 4.2 "Dietary and Lifestyle factors affecting fertility" add two new paragraphs, respectively on Smoke (tobacco and surrogates) and Recreational drugs (marijuana and analogues), and add something more on Folic Acid (Section 4.3.3.), the Review would result more complete and probably represent one of the most complete and current reference texts on this topic.                      In the attached file I have highlighted some small typographic errors.            The Section "References" needs a careful graphic revision. Sometimes the titles of the papers are written in italics, other times not in italics;  the same happens for the names of the Journals. The pages are sometimes indicated with numbers only, other times with "Pages....". Authors are sometimes mentioned differently (see Ref. 44), etc.    In conclusion, the References must be typographically homogeneous. 

Comments for author File: Comments.pdf

Author Response

Thank you for reviewing our paper. Comments are below.

This Review is interesting, well organized and well written; its Sections are exhaustive, clearly developed and correctly synthetic. The presentation of the main concepts in Table 2 is excellent. I think that, if the Authors in Section 4.2 "Dietary and Lifestyle factors affecting fertility" add two new paragraphs, respectively on Smoke (tobacco and surrogates) and Recreational drugs (marijuana and analogues), and add something more on Folic Acid (Section 4.3.3.), the Review would result more complete and probably represent one of the most complete and current reference texts on this  Thank you – we have added the new section on folic acid. No searches returned on Recreational drugs - but we have added a sub head to detail this and  a line to say that it is beyond the scope of this review (potentially  we will consider a separate review on this topic).

 In the attached file I have highlighted some small typographic errors – thank you very much we have made all of these corrections.           

The Section "References" needs a careful graphic revision. Sometimes the titles of the papers are written in italics, other times not in italics;  the same happens for the names of the Journals. The pages are sometimes indicated with numbers only, other times with "Pages....". Authors are sometimes mentioned differently (see Ref. 44), etc.    In conclusion, the References must be typographically homogeneous.  We have corrected.

Reviewer 3 Report

Reviewer’s report
Manuscript: Dietetics - 1655434
Title: Developing pre-conceptual guidelines for men: a review of male infertility
experience, including nutrition and lifestyle factors 2000-2021
1. General comments:
The authors addressed an important research area of the impact of nutrition and lifestyle on
male fertility. The fact that recent reports indicate a decline in male fertility in the last few
decades has put the spotlight on a number of lifestyle and environmental factors that could
contribute to male infertility. The novelty of this manuscript lies in the fact that the authors aimed
to construct guidelines for men to maximize their potential fertility by avoiding certain potentially
harmful substances or practices and increasing others. Unfortunately, there are some major
shortcomings in the study that should be addressed.
My recommendation is major revision as listed below.
2. Specific comments:
Title and keywords
The title is sufficient and descriptive.
I suggest not to use keywords that already appear in the title and certainly not use the term
“fertility” in three different keywords. Since spermatogenesis was not discussed or reported in
such detail, I suggest that it should be replaced by a term such as “semen parameters” or “semen
quality”.
Abstract
The abstract only includes some of the major discussion points in the review whilst others have
been omitted. For instance, the environmental impact on male fertility is not even mentioned.
Introduction
Many of the concerns on the data used for the upper and lower limits for semen parameters as
indicated in lines 52-60 has been addressed in the latest version of the WHO Manual (6 th edition,
2021) and should be referred to or addressed in the Introduction.
There is no clear aim for the review indicated in the Introduction as well as what the authors wish
to obtain through the information included in the review.
Methodology
The following needs to be clarified in terms of the methodology followed:

2
• Why were only studies published in the time period 2000-2021 included in the initial
search for publications to consider for the review?
• In Table 1 the number of publications included in the narrative review after 3 searches
and additional hand searches. However, the numbers do not add up to the 137 articles
mentioned in the abstract. A clear description of subsequent selection criteria for
elimination of articles and numbers thereof should be indicated.
• It is mentioned that ethical approval was granted for the overall project that this review
form part of. I suggest the aim of the overall project should also be included in order to
understand the basic ideas which resulted in this review being written.
Data analysis
It is unclear from this section how the topics included in the “Findings” section got selected from
the data analysis description. Was it based on what was presented in the 2000-2021 articles
which were scrutinized for this review? If so, how was these topics then deemed more important
than topics which were relevant to the search but was published prior to 2000? My concern is
that the topics covered in the “Findings” is quite random and only address a handful of the myriad
of possible reasons for male infertility which can be linked to nutrition, lifestyle factors and
environmental impact.
Findings
The numbering or organizing of the subheadings in this section is not consequent. It is also not
indicated why “Environmental impacts on male fertility” should be a main heading similar to
“Data analysis” and “Findings” for example.
In section 4.1, instead of just discussing the emotional experience males have when they are
informed about their infertility or sub-fertility, I recommend the authors also include the effect
of stress (e.g. mentally or physically) in actually causing men to become infertile in the first place
– a lifestyle factor often ignored or not optimally assessed. This is also an important guideline to
be included in Table 2.
When th e authors make statements such as “strong evidence is lacking” or “there were no
randomized interventional studies that could be found”, do they refer to the cohort of 2000-2021
articles investigated or in general when scrutinizing a lager pool of publications? Some of the
topics included in this section might have been addressed by studies pre-2000s and will still be
valid in the results that was presented.
In some sections the details of evidence given is much more in depth than in others, e.g. 4.3.3.
versus 4.3.4., and skews the data and evidence the towards the more detailed parts.
Although BPA is a well-known environmental factor and proven to affect fertility, it is once again
not clear why this specific environmental contaminant/EDC was selected for this review (over
and above many similar or even more toxic substances)

3
Conclusion
Table 2 is not referred to in the text and probably should be mentioned in this section.
Furthermore, not all points/guidelines included in the table is related to topics discussed in the
parts of the review prior to the Conclusion. The objectives to construct Table 2 as well as the
selection of guidelines to be included in the table should be added to either the Methodology
section of to the Conclusion.

Author Response

Thank you for reviewing our paper, we have responded below in bold, next to your comments.

General comments:
The authors addressed an important research area of the impact of nutrition and lifestyle on male fertility. The fact that recent reports indicate a decline in male fertility in the last few decades has put the spotlight on a number of lifestyle and environmental factors that could contribute to male infertility. The novelty of this manuscript lies in the fact that the authors aimed to construct guidelines for men to maximize their potential fertility by avoiding certain potentially harmful substances or practices and increasing others. Unfortunately, there are some major shortcomings in the study that should be addressed.
My recommendation is major revision as listed below.
2. Specific comments:
Title and keywords
The title is sufficient and descriptive.
I suggest not to use keywords that already appear in the title and certainly not use the term
“fertility” in three different keywords. Since spermatogenesis was not discussed or reported in such detail, I suggest that it should be replaced by a term such as “semen parameters” or “semen quality”. Thank you – have amended the key words

Abstract
The abstract only includes some of the major discussion points in the review whilst others have been omitted. For instance, the environmental impact on male fertility is not even mentioned. Introduction. Added to introduction of the abstract.

Many of the concerns on the data used for the upper and lower limits for semen parameters as indicated in lines 52-60 has been addressed in the latest version of the WHO Manual (6 th edition, 2021) and should be referred to or addressed in the Introduction. Agreed, we have updated the introduction to reflect this.
There is no clear aim for the review indicated in the Introduction as well as what the authors wish to obtain through the information included in the review. Thank you, we have clarified this in response to other reviewer’s comments too (and linked the psycho-social)
Methodology
The following needs to be clarified in terms of the methodology followed:

2
• Why were only studies published in the time period 2000-2021 included in the initial
search for publications to consider for the review?  Some of the review papers identfied through our searches have considered papers prior to the date range – so we have now amended the article title and  also the methodology to explain this. • In Table 1 the number of publications included in the narrative review after 3 searches
and additional hand searches. However, the numbers do not add up to the 137 articles
mentioned in the abstract. A clear description of subsequent selection criteria for elimination of articles and numbers thereof should be indicated. Searches have been checked, we actually repeated them to be sure and Table 1 has been revised .

• 
  It is mentioned that ethical approval was granted for the overall project that this review
  form part of. I suggest the aim of the overall project should also be included in order to
  understand the basic ideas which resulted in this review being written. We have added this in.
  Data analysis
  It is unclear from this section how the topics included in the “Findings” section got selected from
  the data analysis description. Was it based on what was presented in the 2000-2021 articles
  which were scrutinized for this review? If so, how was these topics then deemed more important
  than topics which were relevant to the search but was published prior to 2000? My concern is
  that the topics covered in the “Findings” is quite random and only address a handful of the myriad
  of possible reasons for male infertility which can be linked to nutrition, lifestyle factors and
  environmental impact. We have reported a synthesis of the main findings returned in the papers identified through our search criteria, we have produced a new table (Table 3) showing more detail about the papers and their main findings. We have added additional detail on the method in section 3.

Findings
The numbering or organizing of the subheadings in this section is not consequent. It is also not
indicated why “Environmental impacts on male fertility” should be a main heading similar to
“Data analysis” and “Findings” for example. Amended.
In section 4.1, instead of just discussing the emotional experience males have when they are
informed about their infertility or sub-fertility, I recommend the authors also include the effect
of stress (e.g. mentally or physically) in actually causing men to become infertile in the first place
– a lifestyle factor often ignored or not optimally assessed. This is also an important guideline to
be included in Table 2. Added in a point about managing stress to table 3 and stress is covered in 4.1
When th e authors make statements such as “strong evidence is lacking” or “there were no
randomized interventional studies that could be found”, do they refer to the cohort of 2000-2021
articles investigated or in general when scrutinizing a lager pool of publications? Some of the
topics included in this section might have been addressed by studies pre-2000s and will still be
valid in the results that was presented. The review papers identfied through our search have considered papers prior to the date – so we have amended the article title and also the methodology to explain this. Our initial searches without dates returned many thousands  of searches so we were advised to  qualify the dates of publication (this is also now referred to in methodology)
In some sections the details of evidence given is much more in depth than in others, e.g. 4.3.3.
versus 4.3.4., and skews the data and evidence the towards the more detailed parts.
Although BPA is a well-known environmental factor and proven to affect fertility, it is once again
not clear why this specific environmental contaminant/EDC was selected for this review (over
and above many similar or even more toxic substances) The contaminants that came up in the searches were Bisphenols, pesticides and Pthalates, possibly due to the search terms and inclusion criteria. For this reason we just focussed on the articles in environmental toxins and male fertility or sperm health that came up in the search results.

3
Conclusion
Table 2 is not referred to in the text and probably should be mentioned in this section.
Furthermore, not all points/guidelines included in the table is related to topics discussed in the
parts of the review prior to the Conclusion. The objectives to construct Table 2 as well as the
selection of guidelines to be included in the table should be added to either the Methodology
section of to the Conclusion. Thank you. We have referred to table 2 in conclusion

Round 2

Reviewer 3 Report

I am satisfied that my previous suggestions and comments have been addressed.

Just a few small editing issues with the revised version:

1. Abstract, line 23: Sentence starting with "Reviewed data indicates..." now does not read well - remove "have been shown".

2. Re-ordering of references are necessary so that numbers follow upon one another in text (e.g. reference 145 should be included earlier in reference list since it is cited at the end of the Introduction).

3. The spelling of "asthenozoospermia" in Table 1 is incorrect.

4. Numbering of the tables should be revised. My suggestion is to label new table as Table 2 (not Table 3) and indicate that it is available as Supplementary Material. Guidelines at end of manuscript should be renamed as Table 3 (already used this number in text to refer to table).

Author Response

Thank you for reviewing our manuscript again. We have made the type corrections on the manuscript (attached)  and corrected the number of the table. The journal will help us further with the references as I am away in remote location and little tech until 11th July.

Author Response File: Author Response.docx