Sterility, an Overlooked Health Condition
Round 1
Reviewer 1 Report
This paper makes an important contribution to the field of sterility. It addresses the current gap in the medical literature on this topic. The lack of focus on this under-researched field has lead to a lack of knowledge on key areas such as prevalence. Importantly, the paper provides a definition of the term and calls for a greater research focus. It is particularly important that patients are given a correct diagnosis of sterility, as this has a significant bearing on fertility treatment outcomes.
The methodology of analyzing primary literature and conducting a meta-analysis on the rates of live births and pregnancies throughout several treatments of infertile couples, appears to have been done in a sound and robust way. The paper has provided a distinct differences in Sterility types such as; natural, clinical and hardship.
Importantly the paper has identified the need for research on the causes of sterility, and to develop methods for diagnosis and treatment that are financially affordable and emotionally tolerable.
I highly recommend this paper for publication.
Author Response
We appreciate the Reviewer for highly recommending this paper for publication.
Reviewer 2 Report
The authors have made an attempt to understand the issue of sterility and infertility in the couples. They have described the terms and also referred to literature that has shown data related to this subject. The review article has described the terms of natural and clinical sterility and also introduce the term of hardship sterility. The article is interesting and there are few comments on the work:
- The authors introduce the terms of "prospectively clinically sterile couple" and "retrospectively clinically sterile" and mention that diagnostic tests should be developed by the researchers. The underlying cause of sterility can be many-fold. It can be either age-related, genetics, environmental or occupational. So, do the authors have any suggestions on the diagnostic test that can help in identifying these potential couples who are unable to give birth? The authors can include some of their suggestions in the section "Understanding sterility will benefit the patient, physician, and researchers".
- It is not recommended to quote information from online resources unless they are strongly backed up with actual studies. For example, the authors describe 'According to online media, “only 1% to 2% of [infertile couples] are sterile, and 50% of infertile couples who seek help, eventually conceive, either naturally or with medical assistance [26].”'. The authors should consider using information and citing it from reliable sources.
- At many places the authors instead of providing numbers, mention relative terms such as "many" to describe the population. For example, "Altogether, based on the literature reviewed above and assuming that the infertile couples in these studies did not receive additional treatments, we estimate that many, if not most, infertile couples are sterile (Figure 4)". If the authors can provide some statistics, it will be more informative and useful to the reader to contextualize the numbers.
- For the studies referred in Table 1 and 2, did those studies report the cause of treatment failure or the cause of unsuccessful pregnancy? The underlying causes will give the readers a better understanding of the reasons for failure to have live births.
- In the title of Figure 1, it should be clinical sterility instead of biological sterility.
Author Response
The authors have made an attempt to understand the issue of sterility and infertility in the couples. They have described the terms and also referred to literature that has shown data related to this subject. The review article has described the terms of natural and clinical sterility and also introduce the term of hardship sterility. The article is interesting and there are few comments on the work:
Answer:
We appreciate the Reviewer find this paper interesting.
The authors introduce the terms of "prospectively clinically sterile couple" and "retrospectively clinically sterile" and mention that diagnostic tests should be developed by the researchers. The underlying cause of sterility can be many-fold. It can be either age-related, genetics, environmental or occupational. So, do the authors have any suggestions on the diagnostic test that can help in identifying these potential couples who are unable to give birth? The authors can include some of their suggestions in the section "Understanding sterility will benefit the patient, physician, and researchers".
Answer:
Thank you for highlighting this issue. We now added a suggested diagnostic test near the end of section 1.
It is not recommended to quote information from online resources unless they are strongly backed up with actual studies. For example, the authors describe 'According to online media, "only 1% to 2% of [infertile couples] are sterile, and 50% of infertile couples who seek help, eventually conceive, either naturally or with medical assistance [26]."'. The authors should consider using information and citing it from reliable sources.
Answer:
Thank you for highlighting this issue. We have added these references.
At many places the authors instead of providing numbers, mention relative terms such as "many" to describe the population. For example, "Altogether, based on the literature reviewed above and assuming that the infertile couples in these studies did not receive additional treatments, we estimate that many, if not most, infertile couples are sterile (Figure 4)". If the authors can provide some statistics, it will be more informative and useful to the reader to contextualize the numbers.
Answer:
Thank you for highlighting this issue. We change the text to make it clear and add value based on the discussion in sections 2.1-2.2.
For the studies referred in Table 1 and 2, did those studies report the cause of treatment failure or the cause of unsuccessful pregnancy? The underlying causes will give the readers a better understanding of the reasons for failure to have live births.
Answer:
Thank you for noticing that. We added this information.
In the title of Figure 1, it should be clinical sterility instead of biological sterility.
Answer:
Thank you for noticing that – we corrected it.
Reviewer 3 Report
In my opinion the authors wrote a trite, naive piece without making their points empirically, scientifically, or convincingly. No indepth presentation of how infertility and sterility are clinically managed was offered. There should have been a discussion of how infertile/sterile patients are currently worked-up and counseled. No mention was made about impotence, which would be relevant for inclusion.
The paper seems to be written in a vacuum without any regard to what is currently happening in the field of reproductive medicine. Further, the majority of the references are embarrassingly dated. Q: did you design the graphs and diagrams or are they taken from some other source? If so, you must cite. Section 3 as written is trite and naive. To a large extent, so is Section 4.
Specifically:
Lines 56-57: who is confused? Line 62: I dont think that there is a "cure" per se for sterility. Suggest change of wording. Line 63: I have no idea what you mean in this sentence. Does one really have to differentiate between "natural sterility" and "clinical sterility"? What benefits/gains would be realized by so doing? Line 70: is "hardship sterility" your new term? Lines 133-134 and 148-149: I believe that there are many tests for infertility and sterility. There are a number of diagnostic tools available to help pinpoint the cause of infertility./sterility. Line 160: what "certain groups"? Line 169: so much knowledge has been accumulated since this meta-analysis was published. Line 173-174: this is not particularly surprising. Line 198: do not include unverified sources in a professional paper. Line 297: you really cant make this statement with any sense of certainty or validity. You are stating it to make your point (or so it seemed to me), which is based on faulty reasoning. I think that the entire premise of this paper is faulty. I just do not think that you make your case well.
Author Response
In my opinion the authors wrote a trite, naive piece without making their points empirically, scientifically, or convincingly. No in depth presentation of how infertility and sterility are clinically managed was offered. There should have been a discussion of how infertile/sterile patients are currently worked-up and counseled. No mention was made about impotence, which would be relevant for inclusion.
Answer:
Thank you for this point. We added a new paragraph in the introduction on how infertility and sterility are clinically managed. We also have added impotence as an example of natural sterility.
The paper seems to be written in a vacuum without any regard to what is currently happening in the field of reproductive medicine.
Answer:
Thank you for this point. We added new information to address this point in the introduction
Further, the majority of the references are embarrassingly dated.
Answer:
Thank you for this point. We have added many more recent papers
Q: did you design the graphs and diagrams or are they taken from some other source? If so, you must cite. Section 3 as written is trite and naive.
Answer:
Thank you for your concern. We designed the graphs and diagrams in Section 3. The source of information used to make them is cited in the figure legend.
To a large extent, so is Section 4. Specifically:
Lines 56-57: who is confused?
Answer:
Thank you for pointing this out. We added further information to better explain this.
Line 62: I don't think that there is a "cure" per se for sterility. Suggest change of wording.
Answer:
Thank you for pointing this out. We replaced "cure" with overcome.
Line 63: I have no idea what you mean in this sentence. Does one really have to differentiate between "natural sterility" and "clinical sterility"? What benefits/gains would be realized by so doing?
Answer:
Thank you for pointing this out. We better explain this part. We added that distinguishing between the two will help to highlight the chances of treatment success and the urgency of direct research
Line 70: is "hardship sterility" your new term?
Answer:
Thank you for pointing this out. The concept of hardship sterility is a new term we coined – we added a clarification for that in the text
Lines 133-134 and 148-149: I believe that there are many tests for infertility and sterility. There are a number of diagnostic tools available to help pinpoint the cause of infertility/sterility.
Answer:
Thank you for pointing this out. We change the text to indicate that there is a need for cutoff values for existing tests.
Line 160: what "certain groups"?
Answer:
Thank you for pointing this out. We eliminated this wording.
Line 169: so much knowledge has been accumulated since this meta-analysis was published.
Answer:
Thank you for pointing this out. We added more recent papers.
Line 173-174: this is not particularly surprising.
Answer:
We are delighted that the Reviewer so clearly agrees with our assessment that "most infertile couples who do not undergo fertility treatment do not conceive". This large proportion may not be surprising for him; however, this is surprising for many researchers in reproductive biology.
Line 198: do not include unverified sources in a professional paper.
Answer:
We agree that unverified sources should not be valued in a professional paper, but we have added this unverified information to indicate a need to know this information as it lacks in the professional literature. We made changes to the text to make this clear.
Line 297: you really cant make this statement with any sense of certainty or validity. You are stating it to make your point (or so it seemed to me), which is based on faulty reasoning. I think that the entire premise of this paper is faulty. I just do not think that you make your case well.
Answer:
Thank you for pointing this out. We eliminated this wording and replaced them with a more moderate statement. We hoop that all the changes we made to the paper are developing a better case.
Reviewer 4 Report
Major points:
Introduction: it is not an introduction but an abstract/summary of the manuscripts' aims. Additionally, there is a lack of references - only 2 positions added at the end (!) of the whole paragraph. It should be rewritten.
line 74: An example of natural sterility is someone born with no sperm - nobody id born with sperm! Please, correct this sentence.
line 105: A fertile couple is a couple that conceives naturally within one year of trying. An infertile couple is one that fails to conceive naturally within one year of trying. - Please discuss this with WHO definition, which is clear and exactly the same. So, it cannot be written here as: 'we propose', because you are not the first ones for this fragment.
Figure 2 - description is too long and is the same as in the main body of the manuscript.
lines 133-152: authors should discuss here possible treatment/diagnostics. Some alghoritm or pathway for patients should be suggested here.
ref. 26 - online media? Please, cite only reliable peer-reviewed manuscripts or books
Table 1 - data newer than 2005 should be also included. 15 years of gap (to 2020) is a huge gap in infertility treatment
line 173: the actual prevalence of sterility in this group is likely higher. - ref? value?
line 179: IUI, and ICSI. - please, add full description when appeared first time in the text
line 197: While there are no peer-reviewed papers on the number of couples that undergo IVF/ICSI, there are four unverified online sources which state that 5% of infertile couples undergo IVF/ICSI [44-47]. - this is not true! You have to check ALL real papers, step by step, and then you will get those data. Then, you can (carefully!) add some online data too. But there is no option without publications! This sentence is also in opposition to the next one, in which authors cited real data...
Figure 3, 5: McLernon, et al., (2016) was split into two time periods. - both are in the same blue color. Please, correct it to get the possibility of differentiation. The whole figure 3 legend is too long and too descriptive. Authors should check in other papers, how to write a good legend, that would not copy the manuscript text, but will remain clear.
line 225: we estimate that many, if not most, infertile couples are sterile - how many in %? It has to be written. It is scientific manuscript, not for the online source!
Figure 4 &: Altogether, based on the literature reviewed above and assuming that the infertile couples in these studies did not receive additional treatments, we estimate that many, if not most, infertile couples are sterile (Figure 4). This is a high rate that is comparable to the most prevalent health conditions, including diabetes and chronic obstructive pulmonary disease [53-55]. - why are you citing other diseases here? Where is the infertility source? Hum Reprod? Fertil Steril? Reproduction? Nature? etc.? Some inappropriate references are here, in the context of % infertility. It is not correct.
line 255: Secondly, this research could lead to the development of clinical sterility diagnostic tools, which currently do not exist, as well as to the eventual development of therapeutics. - It is not true - diagnostic and research tools exist. The problem is with the huge % of MDs, who make treatment only 'looking on patient'. This has to be rewritten and examples of tools have to be described here shortly (a huge amount of data is available, i.e. please use PubMed).
line 297:We estimate the prevalence of sterility to be significantly high - if you estimate something, then add % data. If you have no calculations (btw, it is possible to make them on the basis of literature data, really!)
line 305: Currently, there is no differentiation between natural sterility and clinical sterility, which is due to the lack of a diagnostic test for clinical sterility. - it is not true. Everyone who works with (in)fertility knows the difference and know what to do (or not to do). The problem is that there is no official recognition between 'natural' and 'clinical'. Thus, please rewrite this sentence properly.
References: too old!!! Most of them are very old! It is really inappropriate to cite so many so old papers! Especially in the fact that there is a huge amount of data from last 5 years! The proportion should be changed here - i.e. newest ones (let say since 2010) should take >60-70% of all references cited.
Author Response
Introduction: it is not an introduction but an abstract/summary of the manuscripts' aims. Additionally, there is a lack of references - only 2 positions added at the end (!) of the whole paragraph. It should be rewritten.
Answer:
Thank you for pointing this out. We added a new section and modified the introduction.
line 74: An example of natural sterility is someone born with no sperm - nobody id born with sperm! Please, correct this sentence.
Answer:
Thank you for pointing this out. We corrected that.
line 105: A fertile couple is a couple that conceives naturally within one year of trying. An infertile couple is one that fails to conceive naturally within one year of trying. - Please discuss this with WHO definition, which is clear and exactly the same. So, it cannot be written here as: 'we propose', because you are not the first ones for this fragment.
Answer:
Thank you for pointing this out. We corrected that.
Figure 2 - description is too long and is the same as in the main body of the manuscript.
Answer:
Thank you for pointing this out. We shorten Figure 2 legend.
lines 133-152: authors should discuss here possible treatment/diagnostics. Some alghoritm or pathway for patients should be suggested here.
Answer:
Thank you for pointing this out. We change the text to describe a need for cutoff values for existing tests and the need to add functional tests and multi-parametric tests of the sperm.
ref. 26 - online media? Please, cite only reliable peer-reviewed manuscripts or books
Answer:
Thank you for highlighting this issue. We have added reliable peer-reviewed manuscripts.
Table 1 - data newer than 2005 should be also included. 15 years of gap (to 2020) is a huge gap in infertility treatment
Answer:
Thank you for pointing this out. We have added more recent papers.
line 173: the actual prevalence of sterility in this group is likely higher. - ref? value?
Answer:
Thank you for pointing this out. We correct this section and provided values throughout the paper.
line 179: IUI, and ICSI. - please, add full description when appeared first time in the text
Answer:
Thank you for pointing this out. We correct that.
line 197: While there are no peer-reviewed papers on the number of couples that undergo IVF/ICSI, there are four unverified online sources which state that 5% of infertile couples undergo IVF/ICSI [44-47]. - this is not true! You have to check ALL real papers, step by step, and then you will get those data. Then, you can (carefully!) add some online data too. But there is no option without publications! This sentence is also in opposition to the next one, in which authors cited real data...
Answer:
Thank you for pointing this out. We correct that.
Figure 3, 5: McLernon, et al., (2016) was split into two time periods. - both are in the same blue color. Please, correct it to get the possibility of differentiation. The whole figure 3 legend is too long and too descriptive. Authors should check in other papers, how to write a good legend, that would not copy the manuscript text, but will remain clear.
Answer:
Thank you for pointing this out. We correct that.
line 225: we estimate that many, if not most, infertile couples are sterile - how many in %? It has to be written. It is scientific manuscript, not for the online source!
Answer:
Thank you for pointing this out. We now added a specific value.
Figure 4 &: Altogether, based on the literature reviewed above and assuming that the infertile couples in these studies did not receive additional treatments, we estimate that many, if not most, infertile couples are sterile (Figure 4). This is a high rate that is comparable to the most prevalent health conditions, including diabetes and chronic obstructive pulmonary disease [53-55]. - why are you citing other diseases here? Where is the infertility source? Hum Reprod? Fertil Steril? Reproduction? Nature? etc.? Some inappropriate references are here, in the context of % infertility. It is not correct.
Answer:
Thank you for pointing this out. We intended to use the other diseases to highlight the importance of sterility, but since it is confusing to the Reviewer, we have eliminated this sentence and the references to other conditions. Instead, we added a calculation of sterility prevalence, as was requested by the 3rd Reviewer.
line 255: Secondly, this research could lead to the development of clinical sterility diagnostic tools, which currently do not exist, as well as to the eventual development of therapeutics. - It is not true - diagnostic and research tools exist. The problem is with the huge % of MDs, who make treatment only 'looking on patient'. This has to be rewritten and examples of tools have to be described here shortly (a huge amount of data is available, i.e. please use PubMed).
Answer:
Thank you for pointing this out. We have corrected that. We point out that there is a need to determine official cutoff valiues for clinical sterility to existing diagnostic tests and develop comprehensive functional and multi-parametric diagnostic tools.
line 297: We estimate the prevalence of sterility to be significantly high - if you estimate something, then add % data. If you have no calculations (btw, it is possible to make them on the basis of literature data, really!)
Answer:
Thank you for pointing this out. We now added a specific value.
line 305: Currently, there is no differentiation between natural sterility and clinical sterility, which is due to the lack of a diagnostic test for clinical sterility. - it is not true. Everyone who works with (in)fertility knows the difference and know what to do (or not to do). The problem is that there is no official recognition between 'natural' and 'clinical'. Thus, please rewrite this sentence properly.
Answer:
Thank you for pointing this out. We have corrected that.
References: too old!!! Most of them are very old! It is really inappropriate to cite so many so old papers! Especially in the fact that there is a huge amount of data from last 5 years! The proportion should be changed here - i.e. newest ones (let say since 2010) should take >60-70% of all references cited.
Answer:
Thank you for pointing this out. We have added multiply recent papers.
Round 2
Reviewer 4 Report
The manuscript has been improved by the authors. However, still in some parts some newer publications from good sources should be included (i.e. lines: 30-36 only 1 paper from 2018!).
Author Response
The manuscript has been improved by the authors. However, still in some parts some newer publications from good sources should be included (i.e. lines: 30-36 only 1 paper from 2018!).
Answer:
We apologize for missing some sections in the paper that did not provide updated references. We went through the manuscript and introduced 16 new references. These references make the same point cited from older paper so there was only minimal change to the text.
Below are the 16 new references added:
Lines 34
Khan, Iqbal et al. 2019.
Miner, Daumler et al. 2019
Tyuvina and Nikolaevskaya
Line 36-
Grube 2019. Onyedibe,
Aliche et al. 2019
Line 37-
Banerjee and Singla 2018.
Kerckhof, Van Parys et al. 2020
Line 115-
Tanbo and Fedorcsak 2017
Yang, Guo et al. 2018
Mohamed, Shalaby et al. 2018
Line 116-
Lundy and Sabanegh Jr 2018
Line 165-
Pacheco and Oktay 2017
Line 167-
Eken and Gulec 2018
Line 327-
Baudin, T., D. De La Croix, and P.E. Gobbi 2015
Two new sources were added to Table 2 as well:
Hajder, M., E. Hajder, and A. Husic, 2016
van Eekelen, R et.al 2018
