PGPH-D-21-00300

Prevalence and determinants of low testosterone levels in Type II diabetes mellitus men; a case-control study in a district hospital in Ghana

PLOS Global Public Health

Dear Dr. Serwaa,

Thank you for submitting your manuscript to PLOS Global Public Health. After careful consideration, we feel that it has merit but does not fully meet PLOS Global Public Health’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

 

Please consider incorporating the comments of all reviewers.

Please submit your revised manuscript by 05 September, 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at globalpubhealth@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pgph/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Palash Chandra Banik, MPhil

Academic Editor

PLOS Global Public Health

Journal Requirements:

Additional Editor Comments (if provided):

- Please ensure the language editing throughout the manuscript.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does this manuscript meet PLOS Global Public Health’s publication criteria? Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe methodologically and ethically rigorous research with conclusions that are appropriately drawn based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available (please refer to the Data Availability Statement at the start of the manuscript PDF file)?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS Global Public Health does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Authors try to find the prevalence and detrimental effect of testosterone levels in type 2 diabetes patients by case control study population. Previously, many studies were reported the increased testosterone levels in type 2 diabetes patients like "Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis"

however, the present study findings are specific to the ghana city. The provided information is not a new information and novelty of the study was not observed.

Few minor corrections:

Type II diabetes need to be replaced with type 2 diabetes mellites.

articles needs to be written well Like, line 25 The should be capital

Line 374 it is written that cross sectional study and before it is written as case control study. Need a clarity on this.

Table 3 Odd ratio is missing.

Reviewer #2: Dr. Serwaa and colleagues present a detailed case control study of 300 men with type 2 diabetes mellitus and average normal weight for low testosterone in a district hospital within a peri-urban setting, finding significant associations in this populations as shown in a prior urban setting in Ghana. Their results contribute to the literature associating type 2 diabetes and dysglycemia with male hypogonadism, in this case in a peri-urban setting of Nkenkaasu Hospital in Nkenkaasu, Ghana, West Africa in a distinct population from prior studies that contributes to the global understanding of male hypogonadism prevalence. A particular finding of interest is that both their case and control cohorts of moderate size where of normal weight on average, with their diabetes group having suboptimal glycemic control by A1c (8.06) and lower BMI (23.05) than their control group. Strengths also include measurement of pituitary hormones LH and FSH which are lower in the diabetes group, suggesting a relative secondary hypogonadism compared to the control cohort and consistent with hypogonadism occurring in type 2 diabetes. The results presented are complete, the statistical analysis is rigorous and the study was conducted following Declaration of Helsinki ethical principles. Figures 1 and 2 are particularly informative as the convey the variation in testosterone levels in relation to fasting blood glucose and HbA1c. The discussion is nicely written and cites relevant literature including articles documenting similar associations in the Ghanian population as well as the Endocrine Society guidelines as applied in this population. The authors acknowledge limitations of the study including difficulty measuring testosterone in this community due to lack of treatment access, and lack of estradiol measurement.

--Major Issues

*Title: The current title is worded awkwardly and should use person-first language such as “"Prevalence and determinants of low testosterone levels in men with Type II diabetes mellitus; a case-control study in a district hospital in Ghana"

*Assay: The methodological description of the assay AccuDiag Testosterone Assay Kit suggests using a total testosterone measurement, but the authors later refer to free testosterone in the results section. Could the authors clarify if they measured total, free or both testosterone levels? Male hypogonadism in insulin resistance partially involves a decrease in SHBG lowering total testosterone levels, but preserving intact free testosterone levels. This distinction is important as the ELISA assay is different than the commonly accepted LC-MS assays used in other parts of the world that report both free and total testosterone levels.

*Results – One of the more interesting findings of the study is that the diabetes cohort had a lower BMI than the control cohort. Could the authors comment on reasons as to why this might be a difference? Could it be attributed to stage of type 2 diabetes, poor control and subsequent glucosuria, or other factors?

*Results – Dysglycemia occurs in a spectrum, and the authors likely observed similar gonadal deficiencies in subjects with prediabetes as part of clinical care. Could the authors comment on how the observed association would be affected by prediabetes in their population, or as a future study?

*Reporting standards – As a reviewer I would ask the authors to complete the STROBE statement checklist for ease of review (https://www.strobe-statement.org/index.php?id=strobe-home). Most of the elements are included in the document, but the checklist would simplify review and compliance checking. Unfortunately I was not able to review the supplemental material in the RAR or data.sav file provided.

--Minor Issues

*I would suggest organizing the manuscript with the text first and tables at the end per usual manuscript submission guidelines.

*There are minor grammatical spelling errors that can be corrected with editorial assistance. The list below is not exhaustive:

Page 13, lines 216-217: Sentence should be corrected to “The body mass index (BMI) of the healthy controls was significantly higher than...”

Page 15, line 258: Sentence should start with “The distribution…"

Page 22: Line 326: Sentence should be corrected to “Author SD conceived the study.”

Reviewer #3: Definitely this is a great study and the authors hard work should be paid off. Worldwide such type of study is really limited. But the population age is a matter here. Normally within aging the gonads normally begin to do less performance. At this study, population age ranges from 40 - 70 years. Naturally, gonadal function will be decreased. But the main outcome of the study is all right, healthy individuals showed normal testosterones level than the diabetic population. If the population age is limited to 18 from 50, then more scientific evidence can be created which obviously can help on reproductive and over all life outcome. However, this study will also generate evidence. But, i found several lines and write up as out of the main flaws. Here are my comments-

INTRODUCTION:

1. Line no-61: Why loss of memory, depression, lack of concentration will come first over riding the main affects of hypogonadism? I would like to request the author to organize the line accordingly with proper citation.

2. What does the author mean by " Physical decline". Please clarify

3. Type-2 DM is written differently in all over the manuscript. I would request to use one uniform pattern.

STUDY PARTICIPANTS:

1. Cut off values for fasting blood sugar and HBA1c is adopted from where? Any reference, then author should mention it. Because different guidelines use different cut off values.

2. Study participant selection criteria should be more clear.

BODY MASS INDEX- Authors have categorized according to WHO BMI Category? But why no citation or acknowledgement?

BP MEASUREMENT- Line no 124 and whole procedure of BP measurement were done maintain a standard procedure. So, why no citation or acknowledgement?

BLOOD SAMPLE COLLECTION- This procedure is also done maintaining standard protocol. Is it? Clear writing and proper citation is very necessary here.

LABORATORY ASSAY- Are the whole cut off/ normal values are taken from standard guideline? Nothing is clear over there. If yes, then acknowledgement is required.

RESULS:

1. Most of the study participants were at the age group of 40 to 70 years. Normally gonadal function diminishes at this ages. Although a clear explanation is given on the discussion part, but i found it as not enough. It should be more clarified along with some evidences from published studies.

2. Erectile dysfunction rate is quite high and it seems normal at this age group. But the normal individual is also fall into that category. A clear explanation on this finding is very necessary to make the statement reader palatable.

DISCUSSION:

This part is quite good and have made many things clear. But still there are few scope to make it more synchronized with the findings from analysis.

Conclusion:

Few lines were beautifully written. But last portion is quite hazy and it demands re- write maintaining a flaws with the overall study.

ABSTRACT and TITLE: This is quite good and well Witten. But, again the conclusion should be more specified .

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PGPH-D-21-00300R1

Prevalence and determinants of low testosterone levels in men with Type 2 diabetes mellitus; a case-control study in a district hospital in Ghana.

PLOS Global Public Health

Dear Dr. Serwaa,

Thank you for submitting your manuscript to PLOS Global Public Health. After careful consideration, we feel that it has merit but does not fully meet PLOS Global Public Health’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Dear Authors, Kindly address all the points raised by the reviewers.

==============================

Please submit your revised manuscript by 15 October, 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at globalpubhealth@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pgph/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Palash Chandra Banik, MPhil

Academic Editor

PLOS Global Public Health

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

Dear Authors

Please address the reviewers comments accordingly.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Does this manuscript meet PLOS Global Public Health’s publication criteria? Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe methodologically and ethically rigorous research with conclusions that are appropriately drawn based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available (please refer to the Data Availability Statement at the start of the manuscript PDF file)?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS Global Public Health does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: authors clarified and modified according to our comments

Reviewer #2: Comments to the author:

Dr. Serwaa and colleagues present a detailed case control study of 300 men with type 2 diabetes mellitus and average normal weight for low testosterone in a district hospital within a peri-urban setting, finding significant associations in this populations as shown in a prior urban setting in Ghana. Their results contribute to the literature associating type 2 diabetes and dysglycemia with male hypogonadism, in this case in a peri-urban setting of Nkenkaasu Hospital in Nkenkaasu, Ghana, West Africa in a distinct population from prior studies that contributes to the global understanding of male hypogonadism prevalence. A particular finding of interest is that both their case and control cohorts of moderate size were of normal weight on average, with their diabetes group having suboptimal glycemic control by A1c (8.06) and lower BMI (23.05) than their control group. Strengths also include measurement of pituitary hormones LH and FSH which are lower in the diabetes group, suggesting a relative secondary hypogonadism compared to the control cohort and consistent with hypogonadism occurring in type 2 diabetes. The results presented are complete, the statistical analysis is rigorous and the study was conducted following Declaration of Helsinki ethical principles. Figures 1 and 2 are particularly informative as the convey the variation in testosterone levels in relation to fasting blood glucose and HbA1c. The discussion is nicely written and cites relevant literature including articles documenting similar associations in the Ghanian population as well as the Endocrine Society guidelines as applied in this population. The authors acknowledge limitations of the study including difficulty measuring testosterone in this community due to lack of treatment access, and lack of estradiol measurement.

I appreciate the inclusion of the STROBE checklist for case-control studies, and have no additional changes to suggest to the authors.

Reviewer #3: Authors hard work and determination is praiseworthy. They have addresses all the comments raised by the reviewers and it has shaped the manuscript into a more attractive form. But still i have noticed few things are not on that standard. These comments are below

# Objectives and rationale of the study is still hazy. Last part of introduction is not well written and is giving a discrete essence.

#Sample size is less, so it is really difficult to address the title as prevalence study. It is only a proportion from small samples.

#Age group of the study may create a dilemma.

#Despite of having standard cot of values from ADA, WHO authors have used so many secondary references. I personally not in a favor to use this.

#Could not co-relate the line no 130 with the citation number 14.

#Line 193-195 demands an acknowledgement, but this is absent there i see.

#Discussion and conclusion is well in re-written form

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

Do you want your identity to be public for this peer review? If you choose “no”, your identity will remain anonymous but your review may still be made public.

For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Jose O. Aleman

Reviewer #3: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Prevalence and determinants of low testosterone levels in men with Type 2 diabetes mellitus; a case-control study in a district hospital in Ghana.

PGPH-D-21-00300R2

Dear Dr. Serwaa,

We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you'll receive an e-mail detailing the required amendments. When these have been addressed, you'll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at https://www.editorialmanager.com/pgph/ click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they'll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact globalpubhealth@plos.org.

Kind regards,

Palash Chandra Banik, MPhil

Academic Editor

PLOS Global Public Health

Additional Editor Comments (optional):

Dear Authors, Please reply the reviewer comments if any.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

**********

2. Does this manuscript meet PLOS Global Public Health’s publication criteria? Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe methodologically and ethically rigorous research with conclusions that are appropriately drawn based on the data presented.

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available (please refer to the Data Availability Statement at the start of the manuscript PDF file)?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS Global Public Health does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: Authors hard work is praiseworthy. All comments are addressed and the new form of manuscript is better understandable.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

Do you want your identity to be public for this peer review? If you choose “no”, your identity will remain anonymous but your review may still be made public.

For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: Yes: Fardina Rahman Omi

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