Coenzyme Q10 and Melatonin for the Treatment of Male Infertility: A Narrative Review
, Carlo Silvani 1, Matteo Turetti 1, Franco Gadda 1, Paola Viganò 3, Edgardo Somigliana 3,4, Emanuele Montanari 1,4 and Luca Boeri 1,*Round 1
Reviewer 1 Report
General Comments: This narrative review focusses on coenzyme Q10 and melatonin for the treatment of male infertility. Surprisingly, the coenzyme Q10 section of this manuscript is very similar to a recent review (Salvio G et al. Coenzyme Q10 and Male Infertility: A Systematic Review. Antioxidants. 10(6):874. 2021). Both reviews report on the same literature and present similar summary Tables. However the Salvio et al. (2021) review provides a more complete and critical evaluation of the literature than does this manuscript. This raises the question regards the need to publish the coenzyme Q10 section of the current manuscript. Further, there are several inconsistencies in style and content between the coenzyme Q10 and melatonin sections. It appears that these sections were written by different authors and tacked together without careful integration. For example, the melatonin section refers to review articles, has no summary Table, cites animal and in vitro literature, and cites literature older than the year 2000. In contrast, the coenzyme Q10 section cites no review articles (although they exist), has two summary Tables, cites only human studies and cites more recent articles with no reference to older literature (which also exists). These inconsistencies should also be addressed.
Specific Comments:
Abstract, Line 16-17. The sentence states that literature search was conducted for literature published from 2010 to 2022. And yet, both sections of the review cite references older than 2010. See first three studies listed in Table 1 for example. Why?
Abstract Line 21. Define ART.
Page1, Line 41 Change “…associated to infertility” to “… associated with infertility”
Page 2, Line 45. Change “In this regard, number of studies..” to “In this regard, a number of studies…”
Page 2, line 45-47. Sentence refers to “a number of studies” and yet only one study was cited to support the statement. Please add extra citations.
Page 2, Line 59. The following needs rewording as it does not make sense. “…thus resulting indispensable for energy-dependent processes..”
Page 2, Lines 72-74. “We decided to limit the search to articles published from January 2010 to September 2022, in order to guarantee the relevance and up-to-dateness of the paper.” So how come studies dated from 2004 and 2009 are included in Table1? Also, several studies in Melatonin section of review are older than 2010?
Page 2, Line 73. Change “up-to-dateness” to currency
Page 2, Lines 77-78. “In vitro, animal and human articles were included”. Is this statement correct, given no in vitro or animal studies were reported in coenzyme Q10 section of review?
Page 3, Line 92. “Balercia et. al. investigated …” Which Balercia et. al. reference is being referred to here? Is this the expected referencing style.
Page 3, Line 101. “ (47.8 ± 11.2 × 106 vs. 57.6 ± 14.4 × 106, p = 0.01)”. Superscript the 106 so it reads (47.8 ± 11.2 × 106 vs. 57.6 ± 14.4 × 106, p = 0.01). This error is found in many other places throughout the manuscript, so please check and fix.
Page 3, line 116. “(20.1 ± 4.5% vs. 28.4 ± 4.9, p = 0.03) add percent symbol to read ..( (20.1 ± 4.5% vs. 28.4 ± 4.9%, p = 0.03).
Page 3, line 125. “affected by iOAT.” Define iOAT.
Page 4. Table 1 …” Balercia et al., 2004” Where is this reference in reference list at end of manuscript?
Page 4, Table 1. …Change “CoQ10 30 mg/day “ to "CoQ10 300 mg/day"
Page 4, Table 1. ….For Nadjarzadeh et al., 2011 citation please add to main results column that this study showed non-significant changes in semen parameters in the CoQ10 group.
Page 4, Table 1… In the Safarinejad et al., 2012 study they actually used ubiquinol (a reduced form of CoQ10) rather than CoQ10 (also known as ubiqinone). Should the actual molecule used be reported? If so, please check carefully as other studies that have been cited in Table 1 and 2 have also used ubiquinol. And if not, why not?
Page 4, Table 1. Have the acronymns FSH and LH been defined?
Page 4, Table 1. “Increased atalase and SOD activity and lower seminal plasma 8-isoprostane concentration” Is atalase actually catalase? If so, should it be shortened to CAT?
Page 5, Table 1. “In both groups increase in TAC*, CAT and SOD activity” what is the asterisk supposed to denote?
Page 5, Line 135. “Table 1 Summary of tudies…” should read “Table 1 Summary of studies…”
Page 5, line 144. “…observed and increase” …Should read “observed an increase”
Page 5, Line 152. ….”.. respectively). total and type B motility …” should read … respectively). Total and type B motility …”
Page 5, line 165……”.. 0.003) all significantly raised [39].” Should read…” ..0.003) all were significantly raised [39].
Page 5, lines 137-168. So why have the authors chosen to discuss results of 6 studies and ignore the other six studies presented in Table 2? Furthermore, the discussion of the six studies is little more than that presented in the Table, raising the question of the need for such repetition. One would expect more of a critique of this literature given it is not clear what role if any CoQ10 is playing as the studies involved a mixture of antioxidant compounds and in quite a few studies the dose of CoQ10 is very low compared with studies investigating CoQ10 on its own.
Page 7, Table 2. “B9 234 mcg” and “B12 2 mcg” What is mcg?
Page 7, line 174. “Table 2 studies evaluating” Should read ..” Table 2 Studies evaluating…”
Page 7, line 185-186. “seminal fluid in a from 2011 by..” Does not make sense.
Page 8, line 193. “In 2015 Gual-Frau et al….” Why isn’t this study included in Table 2?
Page 8, line 195. “..lead to a non-significant 22.1% decrease in SDF (p = 0.02) and..” Given p value is less than 0.05, surely this is considered significant?
Page 8, line 213. “Different authors have described an increase in pregnancy rates after CoQ10 administration [47,48]” In contrast to this statement a meta-analysis (Lafuente et al. 2013) did not report an increase in pregnancy rates – Discuss?
Lafuente et al. Coenzyme Q10 and male infertility: a meta-analysis. J Assist Reprod Genet. 2013 Sep; 30(9): 1147–1156.
Page 8, line 236. Why is there no summary Table of studies for melatonin as per the CoQ10 section of review?
Page 8, line 239. Define GnRH.
Page 8, lines 239-240. “Moreover. Furthermore, …” Please fix.
Page 9, lines 245 and 247. Define DHT and CRH.
Page 9, line 283. “For instance, in a systematic review and meta-analysis from 2020, Hu and” So in the melatonin section of review systematic and meta-analyses are considered and discussed but not in the CoQ10 section. Why?
Page 9, Line 286. “Moreover, Zhang Besides these …” Does not make sense.
Author Response
Prof. Dr. Giorgio Ivan Russo
Prof. Dr. Giuseppe Grosso
Guest Editors
Impact of Diet and Nutrition on Male Reproductive Health
Milan, October 16th 2022
Dear Editors,
Please fined enclosed the revised version of the manuscript “Coenzyme Q10 and melatonin for the treatment of male infertility: a narrative review?” to be considered for publication in Nutrients.
We are very grateful to the Reviewers for their insightful comments to our paper.
List of the changes made in the manuscript:
REVIEWER #1
COMMENT#1.
There are several inconsistencies in style and content between the coenzyme Q10 and melatonin sections. It appears that these sections were written by different authors and tacked together without careful integration. For example, the melatonin section refers to review articles, has no summary Table, cites animal and in vitro literature, and cites literature older than the year 2000. In contrast, the coenzyme Q10 section cites no review articles (although they exist), has two summary Tables, cites only human studies and cites more recent articles with no reference to older literature (which also exists). These inconsistencies should also be addressed.
A1. We thank the Reviewer#1 for this comment. The text has been revised accordingly.
COMMENT#2.
Abstract, Line 16-17. The sentence states that literature search was conducted for literature published from 2010 to 2022. And yet, both sections of the review cite references older than 2010. See first three studies listed in Table 1 for example. Why?
A2. We thank the Reviewer#1 for this comment. The actual search was done between 2000 and 2022. That was a typo. The text has been revised accordingly
COMMENT#3.
Abstract Line 21. Define ART.
A3. The text has been revised accordingly
COMMENT#4.
Page1, Line 41 Change “…associated to infertility” to “… associated with infertility”
Page 2, Line 45. Change “In this regard, number of studies..” to “In this regard, a number of studies…”
Page 2, line 45-47. Sentence refers to “a number of studies” and yet only one study was cited to support the statement. Please add extra citations.
Page 2, Line 59. The following needs rewording as it does not make sense. “…thus resulting indispensable for energy-dependent processes..”
Page 2, Lines 72-74. “We decided to limit the search to articles published from January 2010 to September 2022, in order to guarantee the relevance and up-to-dateness of the paper.” So how come studies dated from 2004 and 2009 are included in Table1? Also, several studies in Melatonin section of review are older than 2010?
Page 2, Line 73. Change “up-to-dateness” to currency
A4. We thank the Reviewer#1 for this comment. We have revised the text accordingly.
COMMENT#5.
Page 2, Lines 77-78. “In vitro, animal and human articles were included”. Is this statement correct, given no in vitro or animal studies were reported in coenzyme Q10 section of review?
A5. We thank the Reviewer#1 for this comment. In vitro and animal studies have been considered for the melatonin section.
COMMENT#6.
Page 3, Line 92. “Balercia et. al. investigated …” Which Balercia et. al. reference is being referred to here? Is this the expected referencing style.
Page 3, Line 101. “ (47.8 ± 11.2 × 106 vs. 57.6 ± 14.4 × 106, p = 0.01)”. Superscript the 106 so it reads (47.8 ± 11.2 × 106 vs. 57.6 ± 14.4 × 106, p = 0.01). This error is found in many other places throughout the manuscript, so please check and fix.
Page 3, line 116. “(20.1 ± 4.5% vs. 28.4 ± 4.9, p = 0.03) add percent symbol to read ..( (20.1 ± 4.5% vs. 28.4 ± 4.9%, p = 0.03).
Page 3, line 125. “affected by iOAT.” Define iOAT.
A6. The text has been revised according to your suggestions.
COMMENT#7.
Page 4. Table 1 …” Balercia et al., 2004” Where is this reference in reference list at end of manuscript?
A7. We thank the Reviewer#1 for this comment. This was a pilot study that was not included in the final version of the manuscript. The table has been revised accordingly.
COMMENT#8.
Page 4, Table 1. …Change “CoQ10 30 mg/day “ to "CoQ10 300 mg/day"
Page 4, Table 1. ….For Nadjarzadeh et al., 2011 citation please add to main results column that this study showed non-significant changes in semen parameters in the CoQ10 group.
Page 4, Table 1… In the Safarinejad et al., 2012 study they actually used ubiquinol (a reduced form of CoQ10) rather than CoQ10 (also known as ubiqinone). Should the actual molecule used be reported? If so, please check carefully as other studies that have been cited in Table 1 and 2 have also used ubiquinol. And if not, why not?
Page 4, Table 1. Have the acronymns FSH and LH been defined?
Page 4, Table 1. “Increased atalase and SOD activity and lower seminal plasma 8-isoprostane concentration” Is atalase actually catalase? If so, should it be shortened to CAT?
Page 5, Table 1. “In both groups increase in TAC*, CAT and SOD activity” what is the asterisk supposed to denote?
Page 5, Line 135. “Table 1 Summary of tudies…” should read “Table 1 Summary of studies…”
Page 5, line 144. “…observed and increase” …Should read “observed an increase”
Page 5, Line 152. ….”.. respectively). total and type B motility …” should read … respectively). Total and type B motility …”
Page 5, line 165……”.. 0.003) all significantly raised [39].” Should read…” ..0.003) all were significantly raised [39].
A8. We thank the Reviewer#1 for these precise comments. The text has been revised accordingly.
COMMENT#9.
Page 5, lines 137-168. So why have the authors chosen to discuss results of 6 studies and ignore the other six studies presented in Table 2? Furthermore, the discussion of the six studies is little more than that presented in the Table, raising the question of the need for such repetition. One would expect more of a critique of this literature given it is not clear what role if any CoQ10 is playing as the studies involved a mixture of antioxidant compounds and in quite a few studies the dose of CoQ10 is very low compared with studies investigating CoQ10 on its own.
A9. We thank the Reviewer#1 for this important comment. The entire text has been revised accordingly.
COMMENT#10.
Page 7, Table 2. “B9 234 mcg” and “B12 2 mcg” What is mcg?
Page 7, line 174. “Table 2 studies evaluating” Should read ..” Table 2 Studies evaluating…”
Page 7, line 185-186. “seminal fluid in a from 2011 by..” Does not make sense.
A10. We thank the Reviewer#1 for these comments. The text has been revised accordingly.
COMMENT#11.
Page 8, line 193. “In 2015 Gual-Frau et al….” Why isn’t this study included in Table 2?
A11. The study has been included in table 2
COMMENT#12.
Page 8, line 195. “..lead to a non-significant 22.1% decrease in SDF (p = 0.02) and..” Given p value is less than 0.05, surely this is considered significant?
Page 8, line 213. “Different authors have described an increase in pregnancy rates after CoQ10 administration [47,48]” In contrast to this statement a meta-analysis (Lafuente et al. 2013) did not report an increase in pregnancy rates – Discuss?
Lafuente et al. Coenzyme Q10 and male infertility: a meta-analysis. J Assist Reprod Genet. 2013 Sep; 30(9): 1147–1156.
A12. The text has been revised according to your suggestions
COMMENT#13.
Page 8, line 236. Why is there no summary Table of studies for melatonin as per the CoQ10 section of review?
A13. A summary of table for melatonin studies has been included
COMMENT#14.
Page 8, line 239. Define GnRH.
Page 8, lines 239-240. “Moreover. Furthermore, …” Please fix.
Page 9, lines 245 and 247. Define DHT and CRH.
Page 9, line 283. “For instance, in a systematic review and meta-analysis from 2020, Hu and” So in the melatonin section of review systematic and meta-analyses are considered and discussed but not in the CoQ10 section. Why?
Page 9, Line 286. “Moreover, Zhang Besides these …” Does not make sense.
A14. We thank the Reviewer#1 for these comments. The text has been revised accordingly.
Reviewer2
I read with great interest the article of Lucignani et al. entitled: Coenzyme Q10 and melatonin for the treatment of male infertility: a narrative review," which was recently submitted to the Nutrientsjournal for the Special Issue "Impact of Diet and Nutrition on Male Reproductive Health."
Male oxidative stress-induced infertility (MOSI) is a relatively unknown entity for most physicians and is not until recently that it garnered significant interest. Antioxidant supplementation recently emerged as a valuable and efficacious tool in the hands of andrologists to ameliorate sperm parameters. Nevertheless, no specific guideline recommendations could be made relevant to their use thus far.
The authors are to be commended for presenting a well-conducted narrative review study. They aim to summarize all the available evidence regarding the role of CoQ10 and melatonin in the treatment of male infertility.
While much is left to be studied, the authors conveyed the importance of long-term assessment of melatonin in MOSI through reliable and well-designed future clinical studies.
The materials and methods section is sufficiently detailed. The tables presented are pretty descriptive. Overall, the manuscript is well-written, clear, and concise in the greatest part.
Moreover, the study comes from a renowned Italian hospital, in Milan, with vast experience managing infertile patients, which is of great value.
Lastly, the results of both antioxidant compounds seem promising and should be validated in future trials.
COMMENT#1.
I urge the authors to add the following minor amendment, which will better their work. Considering that indiscriminate and empirical use of these compounds can exert detrimental effects through a reduction state, physicians need to be aware of the antioxidant paradox. The latter was termed by Halliwell et al. to describe that the overuse of antioxidants has no preventative or therapeutic effect at all. Hence, Symeonidis et al., in a recent review, highlighted the need for redox balance, thus safeguarding redox homeostasis. This article signifies moderation is the key to optimal sperm regulation.
The authors are advised to add a comment and cite the following article:
o Symeonidis EN, Evgeni E, Palapelas V, Koumasi D, Pyrgidis N, Sokolakis I, Hatzichristodoulou G, Tsiampali C, Mykoniatis I, Zachariou A, Sofikitis N, Kaltsas A, Dimitriadis F. Redox Balance in Male Infertility: Excellence through Moderation-"ΜÎτρον ἄριστον". Antioxidants (Basel). 2021 Sep 27;10(10):1534. doi: 10.3390/antiox10101534.
A1. We thank the Reviewer#2 for this comment. The article has been cited and discussed as suggested.
We hope that the paper is now suitable to be considered for publication in Nutrients.
Sincerely yours,
Luca Boeri on behalf of all the authors
Luca Boeri, M.D.,
IRCCS Foundation Ca’ Granda, Ospedale Maggiore Policlinico, Department of Urology
University of Milan
Via della Commenda 15, 20122 Milan, Italy
Tel. +39 02 55034501; Fax +39 02 50320584
Email: dr.lucaboeri@gmail.com
Reviewer 2 Report
I read with great interest the article of Lucignani et al. entitled: Coenzyme Q10 and melatonin for the treatment of male infertility: a narrative review," which was recently submitted to the Nutrientsjournal for the Special Issue "Impact of Diet and Nutrition on Male Reproductive Health."
Male oxidative stress-induced infertility (MOSI) is a relatively unknown entity for most physicians and is not until recently that it garnered significant interest. Antioxidant supplementation recently emerged as a valuable and efficacious tool in the hands of andrologists to ameliorate sperm parameters. Nevertheless, no specific guideline recommendations could be made relevant to their use thus far.
The authors are to be commended for presenting a well-conducted narrative review study. They aim to summarize all the available evidence regarding the role of CoQ10 and melatonin in the treatment of male infertility.
While much is left to be studied, the authors conveyed the importance of long-term assessment of melatonin in MOSI through reliable and well-designed future clinical studies.
The materials and methods section is sufficiently detailed. The tables presented are pretty descriptive. Overall, the manuscript is well-written, clear, and concise in the greatest part.
Moreover, the study comes from a renowned Italian hospital, in Milan, with vast experience managing infertile patients, which is of great value.
Lastly, the results of both antioxidant compounds seem promising and should be validated in future trials.
I urge the authors to add the following minor amendment, which will better
their work. Considering that indiscriminate and empirical use of these compounds can exert detrimental effects through a reduction state, physicians need to be aware of the antioxidant paradox. The latter was termed by Halliwell et al. to describe that the overuse of antioxidants has no preventative or therapeutic effect at all. Hence, Symeonidis et al., in a recent review, highlighted the need for redox balance, thus safeguarding redox homeostasis. This article signifies moderation is the key to optimal sperm regulation.
The authors are advised to add a comment and cite the following article:
o Symeonidis EN, Evgeni E, Palapelas V, Koumasi D, Pyrgidis N, Sokolakis I, Hatzichristodoulou G, Tsiampali C, Mykoniatis I, Zachariou A, Sofikitis N, Kaltsas A, Dimitriadis F. Redox Balance in Male Infertility: Excellence through Moderation-"ΜÎτρον ἄριστον". Antioxidants (Basel). 2021 Sep 27;10(10):1534. doi: 10.3390/antiox10101534.
Author Response
Prof. Dr. Giorgio Ivan Russo
Prof. Dr. Giuseppe Grosso
Guest Editors
Impact of Diet and Nutrition on Male Reproductive Health
Milan, October 16th 2022
Dear Editors,
Please fined enclosed the revised version of the manuscript “Coenzyme Q10 and melatonin for the treatment of male infertility: a narrative review?” to be considered for publication in Nutrients.
We are very grateful to the Reviewers for their insightful comments to our paper.
List of the changes made in the manuscript:
REVIEWER #1
COMMENT#1.
There are several inconsistencies in style and content between the coenzyme Q10 and melatonin sections. It appears that these sections were written by different authors and tacked together without careful integration. For example, the melatonin section refers to review articles, has no summary Table, cites animal and in vitro literature, and cites literature older than the year 2000. In contrast, the coenzyme Q10 section cites no review articles (although they exist), has two summary Tables, cites only human studies and cites more recent articles with no reference to older literature (which also exists). These inconsistencies should also be addressed.
A1. We thank the Reviewer#1 for this comment. The text has been revised accordingly.
COMMENT#2.
Abstract, Line 16-17. The sentence states that literature search was conducted for literature published from 2010 to 2022. And yet, both sections of the review cite references older than 2010. See first three studies listed in Table 1 for example. Why?
A2. We thank the Reviewer#1 for this comment. The actual search was done between 2000 and 2022. That was a typo. The text has been revised accordingly
COMMENT#3.
Abstract Line 21. Define ART.
A3. The text has been revised accordingly
COMMENT#4.
Page1, Line 41 Change “…associated to infertility” to “… associated with infertility”
Page 2, Line 45. Change “In this regard, number of studies..” to “In this regard, a number of studies…”
Page 2, line 45-47. Sentence refers to “a number of studies” and yet only one study was cited to support the statement. Please add extra citations.
Page 2, Line 59. The following needs rewording as it does not make sense. “…thus resulting indispensable for energy-dependent processes..”
Page 2, Lines 72-74. “We decided to limit the search to articles published from January 2010 to September 2022, in order to guarantee the relevance and up-to-dateness of the paper.” So how come studies dated from 2004 and 2009 are included in Table1? Also, several studies in Melatonin section of review are older than 2010?
Page 2, Line 73. Change “up-to-dateness” to currency
A4. We thank the Reviewer#1 for this comment. We have revised the text accordingly.
COMMENT#5.
Page 2, Lines 77-78. “In vitro, animal and human articles were included”. Is this statement correct, given no in vitro or animal studies were reported in coenzyme Q10 section of review?
A5. We thank the Reviewer#1 for this comment. In vitro and animal studies have been considered for the melatonin section.
COMMENT#6.
Page 3, Line 92. “Balercia et. al. investigated …” Which Balercia et. al. reference is being referred to here? Is this the expected referencing style.
Page 3, Line 101. “ (47.8 ± 11.2 × 106 vs. 57.6 ± 14.4 × 106, p = 0.01)”. Superscript the 106 so it reads (47.8 ± 11.2 × 106 vs. 57.6 ± 14.4 × 106, p = 0.01). This error is found in many other places throughout the manuscript, so please check and fix.
Page 3, line 116. “(20.1 ± 4.5% vs. 28.4 ± 4.9, p = 0.03) add percent symbol to read ..( (20.1 ± 4.5% vs. 28.4 ± 4.9%, p = 0.03).
Page 3, line 125. “affected by iOAT.” Define iOAT.
A6. The text has been revised according to your suggestions.
COMMENT#7.
Page 4. Table 1 …” Balercia et al., 2004” Where is this reference in reference list at end of manuscript?
A7. We thank the Reviewer#1 for this comment. This was a pilot study that was not included in the final version of the manuscript. The table has been revised accordingly.
COMMENT#8.
Page 4, Table 1. …Change “CoQ10 30 mg/day “ to "CoQ10 300 mg/day"
Page 4, Table 1. ….For Nadjarzadeh et al., 2011 citation please add to main results column that this study showed non-significant changes in semen parameters in the CoQ10 group.
Page 4, Table 1… In the Safarinejad et al., 2012 study they actually used ubiquinol (a reduced form of CoQ10) rather than CoQ10 (also known as ubiqinone). Should the actual molecule used be reported? If so, please check carefully as other studies that have been cited in Table 1 and 2 have also used ubiquinol. And if not, why not?
Page 4, Table 1. Have the acronymns FSH and LH been defined?
Page 4, Table 1. “Increased atalase and SOD activity and lower seminal plasma 8-isoprostane concentration” Is atalase actually catalase? If so, should it be shortened to CAT?
Page 5, Table 1. “In both groups increase in TAC*, CAT and SOD activity” what is the asterisk supposed to denote?
Page 5, Line 135. “Table 1 Summary of tudies…” should read “Table 1 Summary of studies…”
Page 5, line 144. “…observed and increase” …Should read “observed an increase”
Page 5, Line 152. ….”.. respectively). total and type B motility …” should read … respectively). Total and type B motility …”
Page 5, line 165……”.. 0.003) all significantly raised [39].” Should read…” ..0.003) all were significantly raised [39].
A8. We thank the Reviewer#1 for these precise comments. The text has been revised accordingly.
COMMENT#9.
Page 5, lines 137-168. So why have the authors chosen to discuss results of 6 studies and ignore the other six studies presented in Table 2? Furthermore, the discussion of the six studies is little more than that presented in the Table, raising the question of the need for such repetition. One would expect more of a critique of this literature given it is not clear what role if any CoQ10 is playing as the studies involved a mixture of antioxidant compounds and in quite a few studies the dose of CoQ10 is very low compared with studies investigating CoQ10 on its own.
A9. We thank the Reviewer#1 for this important comment. The entire text has been revised accordingly.
COMMENT#10.
Page 7, Table 2. “B9 234 mcg” and “B12 2 mcg” What is mcg?
Page 7, line 174. “Table 2 studies evaluating” Should read ..” Table 2 Studies evaluating…”
Page 7, line 185-186. “seminal fluid in a from 2011 by..” Does not make sense.
A10. We thank the Reviewer#1 for these comments. The text has been revised accordingly.
COMMENT#11.
Page 8, line 193. “In 2015 Gual-Frau et al….” Why isn’t this study included in Table 2?
A11. The study has been included in table 2
COMMENT#12.
Page 8, line 195. “..lead to a non-significant 22.1% decrease in SDF (p = 0.02) and..” Given p value is less than 0.05, surely this is considered significant?
Page 8, line 213. “Different authors have described an increase in pregnancy rates after CoQ10 administration [47,48]” In contrast to this statement a meta-analysis (Lafuente et al. 2013) did not report an increase in pregnancy rates – Discuss?
Lafuente et al. Coenzyme Q10 and male infertility: a meta-analysis. J Assist Reprod Genet. 2013 Sep; 30(9): 1147–1156.
A12. The text has been revised according to your suggestions
COMMENT#13.
Page 8, line 236. Why is there no summary Table of studies for melatonin as per the CoQ10 section of review?
A13. A summary of table for melatonin studies has been included
COMMENT#14.
Page 8, line 239. Define GnRH.
Page 8, lines 239-240. “Moreover. Furthermore, …” Please fix.
Page 9, lines 245 and 247. Define DHT and CRH.
Page 9, line 283. “For instance, in a systematic review and meta-analysis from 2020, Hu and” So in the melatonin section of review systematic and meta-analyses are considered and discussed but not in the CoQ10 section. Why?
Page 9, Line 286. “Moreover, Zhang Besides these …” Does not make sense.
A14. We thank the Reviewer#1 for these comments. The text has been revised accordingly.
Reviewer2
I read with great interest the article of Lucignani et al. entitled: Coenzyme Q10 and melatonin for the treatment of male infertility: a narrative review," which was recently submitted to the Nutrientsjournal for the Special Issue "Impact of Diet and Nutrition on Male Reproductive Health."
Male oxidative stress-induced infertility (MOSI) is a relatively unknown entity for most physicians and is not until recently that it garnered significant interest. Antioxidant supplementation recently emerged as a valuable and efficacious tool in the hands of andrologists to ameliorate sperm parameters. Nevertheless, no specific guideline recommendations could be made relevant to their use thus far.
The authors are to be commended for presenting a well-conducted narrative review study. They aim to summarize all the available evidence regarding the role of CoQ10 and melatonin in the treatment of male infertility.
While much is left to be studied, the authors conveyed the importance of long-term assessment of melatonin in MOSI through reliable and well-designed future clinical studies.
The materials and methods section is sufficiently detailed. The tables presented are pretty descriptive. Overall, the manuscript is well-written, clear, and concise in the greatest part.
Moreover, the study comes from a renowned Italian hospital, in Milan, with vast experience managing infertile patients, which is of great value.
Lastly, the results of both antioxidant compounds seem promising and should be validated in future trials.
COMMENT#1.
I urge the authors to add the following minor amendment, which will better their work. Considering that indiscriminate and empirical use of these compounds can exert detrimental effects through a reduction state, physicians need to be aware of the antioxidant paradox. The latter was termed by Halliwell et al. to describe that the overuse of antioxidants has no preventative or therapeutic effect at all. Hence, Symeonidis et al., in a recent review, highlighted the need for redox balance, thus safeguarding redox homeostasis. This article signifies moderation is the key to optimal sperm regulation.
The authors are advised to add a comment and cite the following article:
o Symeonidis EN, Evgeni E, Palapelas V, Koumasi D, Pyrgidis N, Sokolakis I, Hatzichristodoulou G, Tsiampali C, Mykoniatis I, Zachariou A, Sofikitis N, Kaltsas A, Dimitriadis F. Redox Balance in Male Infertility: Excellence through Moderation-"ΜÎτρον ἄριστον". Antioxidants (Basel). 2021 Sep 27;10(10):1534. doi: 10.3390/antiox10101534.
A1. We thank the Reviewer#2 for this comment. The article has been cited and discussed as suggested.
We hope that the paper is now suitable to be considered for publication in Nutrients.
Sincerely yours,
Luca Boeri on behalf of all the authors
Luca Boeri, M.D.,
IRCCS Foundation Ca’ Granda, Ospedale Maggiore Policlinico, Department of Urology
University of Milan
Via della Commenda 15, 20122 Milan, Italy
Tel. +39 02 55034501; Fax +39 02 50320584
Email: dr.lucaboeri@gmail.com
Round 2
Reviewer 1 Report
General Comments: This narrative review focusses on coenzyme Q10 and melatonin for the treatment of male infertility. As I have already indicated, the coenzyme Q10 section of this manuscript is very similar to a recent review (Salvio G et al. Coenzyme Q10 and Male Infertility: A Systematic Review. Antioxidants. 10(6):874. 2021). Both reviews report on the same literature and present similar summary Tables. However the Salvio et al. (2021) review provides a more complete and critical evaluation of the literature than does this manuscript. This problem still remains and therefore raises the question regards the need to publish the coenzyme Q10 section of the current manuscript. The inconsistencies in style and content between the coenzyme Q10 and melatonin sections raised in first review of this manuscript have now been addressed.
Specific Comments:
Abstract, line 24. “… clinical are studies…” should read “.. clinical studies..”
Page 2, line 47. “…sperm cells concentration” should read “ sperm cell concentration”
Page 2, line 49. Define ROS.
Page 2, line 56. “…treatment.[24].” Remove the fullstop after treatment
Page 2, line 64. “…free radicals’ scavengers” should read “…free radical scavengers”
Page 3, line 91. No in vitro or animal studies are reported in the CoQ10 sections of the manuscript. The manuscripts methods state that such studies were to be included. This either means no such studies have been published from 2000 to 2022 and as such this should be clearly stated in these sections. Alternatively, if they have been published they should be reported in the CoQ10 sections of the manuscript. This issue was raised in the first review of this manuscript and has not been adequately addressed.
Page 3, line 104. Define FSH
Page 3, line 105. “….plasma CoQ10 raised after treatment” should read “…plasma CoQ10 were raised after treatment”
Page 4, Table 1. Cakiroglu et al., 2014 and Thakur et al., 2015 studies used ubiquinol as the supplement not ubiquinone. Please fix as has already been done for Safarinejad et al., 2012 study in Table 1.
Page 5, line 142. “114 patients with iOAT…” don’t start sentences with a number. Should read ..”One hundred and fourteen patients…” Same problem occurs on page 6, line 206; page 9, line 245 and page 9, line 252.
Page 5, line 147. “…20 mg coQ10,” should read “…20 mg CoQ10,”
Page 6, lines 183-184. “Both groups did not show any endocrinological or semen parameters increase significantly.” Reword as sentence does not make sense.
Page 6, lines 195. “…active smokers patients to” Reword as it does not make sense.
Page 6, line 198. “..count increase from..” should read “…count increased from..”
Page 6, line 207. “…a 6 months treatment” should read “…a 6 month treatment”
Page 6, line 216. “…Gual-Frau et al., 2015 yesyed the” Please fix.
Page 6, line 217. “…compound with with 20 mg” Remove the extra “with”.
Page 6, section on combination therapy. Please provide a critical analysis of these combination therapy studies in regards how it is unclear which of the antioxidant agents in the supplement cocktail are producing the biological effect. Further, given that many of the studies have used a very low dose of CoQ10 how confident can we be regards whether CoQ10 is having any effect at all in these low dose combination therapies?
Page 7, Table 2. Study by Abad et al., 2013. 1 mcg vitamin B12, 50 mcg selenium. Is the mcg unit correct?
Page 7, Table 2. Study by Gvozdjáková et al., 2015. What is the unit for 440 L-carnitine fumarate?
Page 7, Table 2. Study by Lipovac et al., 2016. “440 mg l-carnitine, 250 mg l-arginine,” should read “440 mg L-carnitine, 250 mg L-arginine,” Note: same error found for studies by Arafa et al. 2020 and Kopets et al 2020 in Table 2. Also “ for3 months” should read “ for 3 months”
Page 7, Table 2. Study by Stenqvist et al., 2018. “vitamin E5 mg,” should read “vitamin E 5 mg,”. Also “coenzyme Q10” abbreviate to CoQ10. Note: same error found for studies by Nazari et al., 2021 and Gual-Frau et al., 2015 in Table 2.
Page 10, Line 296. “…reactive oxygen species production (ROS).” ROS should have already been defined on page 2 line 49.
Page 11, Table 3. Study by Lu et al., 2018. What was the daily dose of melatonin ingested?
Page 12, line 365. “…thus precluding its widespread diffusion” change to “…thus precluding its widespread use”
Page 12, line 374. “…on FIVET success rate” Define FIVET.
Author Response
Prof. Dr. Giorgio Ivan Russo
Prof. Dr. Giuseppe Grosso
Guest Editors
Impact of Diet and Nutrition on Male Reproductive Health
Milan, October 21th 2022
Dear Editors,
Please fined enclosed the revised version of the manuscript “Coenzyme Q10 and melatonin for the treatment of male infertility: a narrative review?” to be considered for publication in Nutrients.
We are very grateful to the Reviewers for their insightful comments to our paper.
List of the changes made in the manuscript:
REVIEWER #1
COMMENT#1.
This narrative review focusses on coenzyme Q10 and melatonin for the treatment of male infertility. As I have already indicated, the coenzyme Q10 section of this manuscript is very similar to a recent review (Salvio G et al. Coenzyme Q10 and Male Infertility: A Systematic Review. Antioxidants. 10(6):874. 2021). Both reviews report on the same literature and present similar summary Tables. However the Salvio et al. (2021) review provides a more complete and critical evaluation of the literature than does this manuscript. This problem still remains and therefore raises the question regards the need to publish the coenzyme Q10 section of the current manuscript. The inconsistencies in style and content between the coenzyme Q10 and melatonin sections raised in first review of this manuscript have now been addressed.
A1. We thank the Reviewer#1 for this comment. We have updated our research query and included also recent literature. Therefore, our narrative review could be considered the most updated review on CoQ10 and melatonin treatment for male infertility.
COMMENT#2.
Abstract, line 24. “… clinical are studies…” should read “.. clinical studies..”
Page 2, line 47. “…sperm cells concentration” should read “ sperm cell concentration”
Page 2, line 49. Define ROS.
Page 2, line 56. “…treatment.[24].” Remove the fullstop after treatment
Page 2, line 64. “…free radicals’ scavengers” should read “…free radical scavengers”
A.2. We thank the Reviewer#1 for these comments. The text has been revised accordingly.
COMMENT#3.
Page 3, line 91. No in vitro or animal studies are reported in the CoQ10 sections of the manuscript. The manuscripts methods state that such studies were to be included. This either means no such studies have been published from 2000 to 2022 and as such this should be clearly stated in these sections. Alternatively, if they have been published they should be reported in the CoQ10 sections of the manuscript. This issue was raised in the first review of this manuscript and has not been adequately addressed.
A.3. We thank the Reviewer#1 for this comment. Only clinical studies have been included. The methods section has been revised accordingly.
COMMENT#4.
Page 3, line 104. Define FSH
Page 3, line 105. “….plasma CoQ10 raised after treatment” should read “…plasma CoQ10 were raised after treatment”
Page 4, Table 1. Cakiroglu et al., 2014 and Thakur et al., 2015 studies used ubiquinol as the supplement not ubiquinone. Please fix as has already been done for Safarinejad et al., 2012 study in Table 1.
Page 5, line 142. “114 patients with iOAT…” don’t start sentences with a number. Should read ..”One hundred and fourteen patients…” Same problem occurs on page 6, line 206; page 9, line 245 and page 9, line 252.
Page 5, line 147. “…20 mg coQ10,” should read “…20 mg CoQ10,”
Page 6, lines 183-184. “Both groups did not show any endocrinological or semen parameters increase significantly.” Reword as sentence does not make sense.
Page 6, lines 195. “…active smokers patients to” Reword as it does not make sense.
Page 6, line 198. “..count increase from..” should read “…count increased from..”
Page 6, line 207. “…a 6 months treatment” should read “…a 6 month treatment”
Page 6, line 216. “…Gual-Frau et al., 2015 yesyed the” Please fix.
Page 6, line 217. “…compound with with 20 mg” Remove the extra “with”.
A.4. We thank the Reviewer#1 for these comments. The text has been revised accordingly.
COMMENT#5.
Page 6, section on combination therapy. Please provide a critical analysis of these combination therapy studies in regards how it is unclear which of the antioxidant agents in the supplement cocktail are producing the biological effect. Further, given that many of the studies have used a very low dose of CoQ10 how confident can we be regards whether CoQ10 is having any effect at all in these low dose combination therapies?
A.5. A critical analysis has been included in the discussion section of the manuscript
COMMENT#6.
Page 7, Table 2. Study by Abad et al., 2013. 1 mcg vitamin B12, 50 mcg selenium. Is the mcg unit correct?
Page 7, Table 2. Study by Gvozdjáková et al., 2015. What is the unit for 440 L-carnitine fumarate?
Page 7, Table 2. Study by Lipovac et al., 2016. “440 mg l-carnitine, 250 mg l-arginine,” should read “440 mg L-carnitine, 250 mg L-arginine,” Note: same error found for studies by Arafa et al. 2020 and Kopets et al 2020 in Table 2. Also “ for3 months” should read “ for 3 months”
Page 7, Table 2. Study by Stenqvist et al., 2018. “vitamin E5 mg,” should read “vitamin E 5 mg,”. Also “coenzyme Q10” abbreviate to CoQ10. Note: same error found for studies by Nazari et al., 2021 and Gual-Frau et al., 2015 in Table 2.
Page 10, Line 296. “…reactive oxygen species production (ROS).” ROS should have already been defined on page 2 line 49.
Page 11, Table 3. Study by Lu et al., 2018. What was the daily dose of melatonin ingested?
Page 12, line 365. “…thus precluding its widespread diffusion” change to “…thus precluding its widespread use”
Page 12, line 374. “…on FIVET success rate” Define FIVET.
A6. We thank the Reviewer#1 for these comments. The text has been revised accordingly
We hope that the paper is now suitable to be considered for publication in Nutrients.
Sincerely yours,
Luca Boeri on behalf of all the authors
Luca Boeri, M.D.,
IRCCS Foundation Ca’ Granda, Ospedale Maggiore Policlinico, Department of Urology
University of Milan
Via della Commenda 15, 20122 Milan, Italy
Tel. +39 02 55034501; Fax +39 02 50320584
Email: dr.lucaboeri@gmail.com
