The Role of Oxytocin in Polycystic Ovary Syndrome: A Systematic Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

Thank you for having the opportunity to review your paper in a field which have not been studied extensively. It is an interesting collection of 5 human and 2 animal studies (but please check results were you write 6 studies and 4 human studies)

However I miss alot of wellknown data and older references

The field of oxytocin in behaviour (social behaviour), depression, anxiety, interaction etc have been studied for many many years which you dont mention. No old references in this field are included. You write that oxytocin is produced in PVN and SON and released into the circulation without mentioning anything about the central pathways of oxytocinergic neurons reaching many important brain areas for behaviour such as other parts of the hypothalamus, amygdala and hippocampus (just to mention a few). You mention in the discussion that autism and pcos have some common behavioural aspects and that oxytocin might be involved. The role for oxytocin in autism is thought to be mediated within the CNS not by peripheral effects by oxytocin. 

I cannot find any discussion about oxytocin levels during the menstrual or ovarial cycle and after menopause. There are several studies (also older) which have shown that oxytocin levels are higher during the preovarial part of the cycle just before ovulation (the follicular phase) and in in rats during estrus. It is also well known that oxytocin is lower in menopausal women compared to premenopausal women (and the same has been shown cycling rats compared to ovx rats). I cannot find any comment about that in the discussion. Estrogen levels increase oxytocin. The results of a correlation of between low oxytocin levels and pcos is interesting but it could also be expected and these aspects should be discussed. 

Alot of old basal references are missing about the correlation between oxytocin and estradiol, effects in cns as discussed above, and also for example the dual effect of oxytocin on food intake and weight. Oxytocin inhibit food intake in both cycling and ovx rats but decrease weight gain only in ovx rats (the effect might also be dose dependent).

Your paper is interesting but should be discussed in the field of already published and known data. 

Comments on the Quality of English Language

English language needs minor correction

Author Response

REVIEWER 1:

Dear authors,

Thank you for having the opportunity to review your paper in a field which have not been studied extensively. It is an interesting collection of 5 human and 2 animal studies (but please check results were you write 6 studies and 4 human studies)

Authors: We are grateful to the reviewer for the commentaries, suggestions, and raised issues that helped to improve our systematic review. We are sorry for this, and we have corrected the results. Please, check the results section.

However I miss a lot of wellknown data and older references

Authors: Thank you. Following your suggestion, we have added the references and the data as you requested.

 

 

The field of oxytocin in behaviour (social behaviour), depression, anxiety, interaction etc have been studied for many many years which you dont mention. No old references in this field are included.

Authors: Thank you. Following your advice, we added the reference as you requested. We added to the introduction the references (also old) about the research field you mentioned. Moreover, we also added data about mood and OT levels, and the administration of OT in sleep disorders, as you can read. Please check Lines [66-70] and the new reference list.

You write that oxytocin is produced in PVN and SON and released into the circulation without mentioning anything about the central pathways of oxytocinergic neurons reaching many important brain areas for behaviour such as other parts of the hypothalamus, amygdala and hippocampus (just to mention a few).

Authors: Thank you. Following your suggestion, we added a specific description of the central pathway of OT.  Since, as widely known the OT cannot pass the blood-brain barrier, the most prevalent hypothesis about the OT pathway was related to a dendritic release in the hypothalamus, followed by a passive diffusion to the target regions in the brain. However, during the last years, tracing studies showed long-range axonal projections of oxytocinergic neurons to several brain regions such as hippocampal subregions and ventral subiculum, shell, and core of nucleus accumbens, island of Calleja, globus pallidus lateral,  lateral septal nucleus, medial amygdaloid nucleus, prelimbic cortex. We rewrite this paragraph in the Introduction, and references have been added. Please, see lines [50-65]

You mention in the discussion that autism and pcos have some common behavioural aspects and that oxytocin might be involved. The role for oxytocin in autism is thought to be mediated within the CNS not by peripheral effects by oxytocin. 

Authors: Thanks for this interesting commentary. Following your suggestion, we found that the statement about autism and its possible association with PCOS was not so intelligible. We added a study that found the OXTR genetic variant rs237902, observed by Amin et al. (included in the present systematic review), associated with autism spectrum disorder (ASD).

 A meta-analysis (Katsigianni et al., 2019) assessed the studies that reported the odds of PCOS women having a child with autism spectrum disorder, and the risk of ASD in women with PCOS. Ten studies have been included and they found that, according to the available evidence, PCOS women have increased odds of having a child with ASD. Regarding the evidence on the prevalence of ASD in PCOS women, results suggest that women with PCOS are more likely to be diagnosed with ASD. Indeed, Hergüner et al (2012) found that women with PCOS had more autistic traits, as measured by the Autism-Spectrum Quotient (AQ). Total AQ and communication scores were statistically higher in women with PCOS.

AQ is a 50-item self-report questionnaire that assesses social skills, communication skills, imagination abilities, attention switching, and attention to detail. AQ shows good psychometric properties.

Please, check the discussion section: lines 344-359. We have also added the following references:

Hergüner, S., Harmancı, H., Hergüner, A., & Toy, H. (2012). Autistic traits in women with polycystic ovary syndrome. Research in Autism Spectrum Disorders, 6(3), 1019-1022.

Katsigianni, M., Karageorgiou, V., Lambrinoudaki, I., & Siristatidis, C. (2019). Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis. Molecular psychiatry, 24(12), 1787-1797.

I cannot find any discussion about oxytocin levels during the menstrual or ovarial cycle and after menopause. There are several studies (also older) which have shown that oxytocin levels are higher during the preovarial part of the cycle just before ovulation (the follicular phase) and in in rats during estrus.

Authors: Thanks. We added a paragraph about the change in OT during the menstrual cycle and estrous in the discussion (lines 286-308).

It is also well known that oxytocin is lower in menopausal women compared to premenopausal women (and the same has been shown cycling rats compared to ovx rats). I cannot find any comment about that in the discussion.

Authors: Thank you. Following your suggestion, we added a paragraph about menopause and OT levels as you requested.

Estrogen levels increase oxytocin. The results of a correlation of between low oxytocin levels and pcos is interesting but it could also be expected and these aspects should be discussed. Alot of old basal references are missing about the correlation between oxytocin and estradiol, effects in cns as discussed above, and also for example the dual effect of oxytocin on food intake and weight. Oxytocin inhibit food intake in both cycling and ovx rats but decrease weight gain only in ovx rats (the effect might also be dose dependent).

Authors: Thank you. Following your suggestion we added some references and a paragraph in the discussion about the OVX rats, oxytocin and food intake. Please check the discussion (lines 245-279)

Your paper is interesting but should be discussed in the field of already published and known data. 

Authors: We are grateful for the positive appraisal and for your comments.

 

Reviewer 2 Report

Comments and Suggestions for Authors

I appreciate the opportunity to review the manuscript entitled “The Role of Oxytocin in Polycystic Ovary Syndrome: a Systematic Review” submitted in journal CIMB.   

The authors reviewed the presence of possible oxytocin level alterations in PCOS, the connection between alterations of OT levels and the symptoms of PCOS, and the effect of oxytocin administration in PCOS. The authors reported that the most of the studies highlighted the role played by oxytocin in fertility issues related to PCOS and the studies confirming a possible implication of a dysfunction of OT, in the pathogenesis of PCOS.

 

Reviewer Comments:

1.      Please prepare list of abbreviations used in manuscript.

2.      The authors need to add some paragraphs about possible molecular link between oxytocin and PCOS.

3.      Please include some data about the link between oxytocin and PCOS related pathologies such as metabolic syndrome, insulin resistance, cardiovascular risk etc.

 

Taking into account the case report and pathology reviewed in above mentioned manuscript, my opinion is that this submission meet the criteria to be published in journal CIMB after minor revisions and inclusion of the data I suggested.

 

Author Response

REVIEWER 2

 

I appreciate the opportunity to review the manuscript entitled “The Role of Oxytocin in Polycystic Ovary Syndrome: a Systematic Review” submitted in journal CIMB.   

The authors reviewed the presence of possible oxytocin level alterations in PCOS, the connection between alterations of OT levels and the symptoms of PCOS, and the effect of oxytocin administration in PCOS. The authors reported that the most of the studies highlighted the role played by oxytocin in fertility issues related to PCOS and the studies confirming a possible implication of a dysfunction of OT, in the pathogenesis of PCOS.

Authors: Thank you for your appraisal, commentaries, and suggestions that have allowed us to improve our manuscript.

 

Reviewer Comments:

1. Please prepare list of abbreviations used in manuscript.

Authors: Thank you. Following your suggestion, we added a list of abbreviations at the end of the manuscript. Please, check “Abbreviations” –Line 410

 

2. The authors need to add some paragraphs about possible molecular link between oxytocin and PCOS.

Authors: Thank you. We agree with you that a possible molecular link between OT and PCOS is very interesting. However, despite the numerous animal and human evidence and the complexity of PCOS, we added a brief paragraph about a possible link between OT and PCOS and a possible negative influence of the low ovarian/uterine levels of OT on the central OT system in the Conclusion. Please check the conclusion, lines 356-382

 

3. Please include some data about the link between oxytocin and PCOS related pathologies such as metabolic syndrome, insulin resistance, cardiovascular risk etc.

 

Authors: Thank you for this commentary, we added previous findings out OT levels and OT administration in metabolic syndrome, cardiovascular risk, mood disorders, and sleep disorders that represent the principal comorbidities observed in PCOS patients. We added the introduction and in the discussion paragraphs about the role played by OT and OXTR in the above-mentioned comorbidities considering both animal and human studies. Please, check the Introduction, lines 79-84, and Discussion, lines 243-277.

 

 

Taking into account the case report and pathology reviewed in above mentioned manuscript, my opinion is that this submission meet the criteria to be published in journal CIMB after minor revisions and inclusion of the data I suggested.

Authors: Thank you for the positive appraisal.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

You have made a great job with the revision of the manuscript. Two minor things in the abstract:

The sentence: Some of the studies highlighted the role played by oxytocin  in fertility issues related to PCOS.

"Some" is a very diffuse word, change to the number of studies instead, for example 2 studies, half of the studies etc.

The sentence: Two human and one animal study agreed about lower levels of PCOS, confirming a possible implication of a dysfunction of OT, in the pathogenesis of PCOS

I suppose it should be "lower levels of oxytocin in PCOS" or do you mean lower levels of symptoms in PCOS?

 

Comments on the Quality of English Language

Check the language once again I think there are minor things to correct but I am not a native English. 

Author Response

Dear Reviewer,

Thank you for your suggestions, and commentaries that improved our manuscript. 

Please, check the new version of the manuscript and the Abstract.

Moreover, we have checked the manuscript for typos and fixed grammatical errors.