Understanding Pain in Polycystic Ovary Syndrome: Health Risks and Treatment Effectiveness

Reviewer #1 (Public review):

Summary:

This retrospective study provides new data regarding the prevalence of pain in women with PCOS and its relationship with health outcomes. Using data from electronic health records (EHR), the authors found a significantly higher prevalence of pain among women with PCOS compared to those without the condition: 19.21% of women with PCOS versus 15.8% in non-PCOS women. The highest prevalence of pain was conducted among Black or African American (32.11%) and White (30.75%) populations. Besides, women with PCOS and pain have at least a 2-fold increased prevalence of obesity (34.68%) at baseline compared to women with PCOS in general (16.11%). Also, women with PCOS had the highest risk for infertility and T2D, but women with PCOS and pain had higher risks for ovarian cysts and liver disease. Regarding these results, the authors suggested the critical need to address pain in the diagnosis and management of PCOS due to its significant impact on patient health outcomes.

Strengths:

(1) The problem of pain assessment in PCOS patients is well described and the authors provided a clear rationale selection of the retrospective design to investigate this problem.

(2) A large number of analyzed patient records (76,859,666 women) and their uniformity increases the power of the study. Using the Propensity Score Matching makes it possible to reduce the heterogeneity of the compared cohorts and the influence of comorbid conditions.

(3) Analysis in different ethnic cohorts provides actual and necessary data regarding the prevalence of pain and its relationship with different health conditions that will be helpful for clinicians to make a diagnosis and manage PCOS in women of different ethnicities.

(4) Assessment of the risk of different health conditions including PCOS-associated pathology as other common groups of diseases in PCOS women with or without pain allows to differentiate the risk of comorbid conditions depending on the presence of one symptom (pelvic or abdominal pain, dysmenorrhea).

Weaknesses:

(1) Although the paper has strengths in methodology and data analysis, it also has some weaknesses. The lack of a hypothesis doesn't allow us to evaluate the aim and significance of this study.

(2) The exclusion criteria don't include conditions, that can lead to symptoms similar to PCOS: thyroid diseases, hyperprolactinemia, and congenital adrenal hyperplasia. Thyroid status is not being taken into account in the criteria for matching. All these conditions could occur as on prevalence results as on risk assessment.

(3) The significant weakness of the study is the absence of a Latin American cohort. Probably the White cohort includes Latin Americans or others, but the results of the study cannot be extrapolated to particular White ethnicities.

(4) The authors didn't provide sufficient rationale for future health outcomes and this list didn't include diseases of the digestive system or disorders of thyroid glands, which can also cause abdominal pain.

Reviewer #2 (Public review):

Summary:

The study offers a thorough analysis of the prevalence of pain in women with polycystic ovary syndrome (PCOS) and its associations with health outcomes across various racial groups. Furthermore, the research investigates the prevalence of PCOS and pain among different racial demographics, as well as the increased risk of developing various conditions in comparison to individuals who have PCOS alone.

Strengths:

The study emphasizes pain as a significant comorbidity of PCOS, an area that is critically underexplored in existing literature. The findings regarding the increased prevalence of some of the diseases in the PCOS + pain group provide valuable direction for future research and clinical care. I believe physicians should incorporate pain score assessments into their clinical practice to improve patient's quality of life and raise awareness about pain management. If future research focuses on the mechanisms of pain, it would provide a better understanding of pain and allow for a focus on the underlying causes rather than just symptomatic management. The study also highlights the association between PCOS+pain and various comorbidities, such as obesity, hypertension, and type 2 diabetes, as well as conditions like infertility and ovarian cysts, offering a holistic view of the burden of PCOS.

Weaknesses:

Due to the nature of the retrospective study, some data may not be readily available in the system. Instead of simply categorizing participants based on whether they experience pain, it would be more useful to employ a pain scale or questionnaire to better understand the severity and type of patients' pain. This approach would allow for a more thorough analysis of pain improvement following treatment with the three widely used medications for PCOS. Additionally, it would be beneficial for the authors to specify subtypes of the disease rather than generalizing conditions, such as mentioning specific digestive system disorders or mental health disorders. The lack of detailed analysis of specific disorders limits the depth of the findings. This may cause authors to make incorrect conclusions.

Author response:

Public Reviews:

Reviewer #1 (Public review):

Summary:

This retrospective study provides new data regarding the prevalence of pain in women with PCOS and its relationship with health outcomes. Using data from electronic health records (EHR), the authors found a significantly higher prevalence of pain among women with PCOS compared to those without the condition: 19.21% of women with PCOS versus 15.8% in non-PCOS women. The highest prevalence of pain was conducted among Black or African American (32.11%) and White (30.75%) populations. Besides, women with PCOS and pain have at least a 2-fold increased prevalence of obesity (34.68%) at baseline compared to women with PCOS in general (16.11%). Also, women with PCOS had the highest risk for infertility and T2D, but women with PCOS and pain had higher risks for ovarian cysts and liver disease. Regarding these results, the authors suggested the critical need to address pain in the diagnosis and management of PCOS due to its significant impact on patient health outcomes.

Strengths:

(1) The problem of pain assessment in PCOS patients is well described and the authors provided a clear rationale selection of the retrospective design to investigate this problem.(2) A large number of analyzed patient records (76,859,666 women) and their uniformity increases the power of the study. Using the Propensity Score Matching makes it possible to reduce the heterogeneity of the compared cohorts and the influence of comorbid conditions.(3) Analysis in different ethnic cohorts provides actual and necessary data regarding the prevalence of pain and its relationship with different health conditions that will be helpful for clinicians to make a diagnosis and manage PCOS in women of different ethnicities. (4) Assessment of the risk of different health conditions including PCOS-associated pathology as other common groups of diseases in PCOS women with or without pain allows to differentiate the risk of comorbid conditions depending on the presence of one symptom (pelvic or abdominal pain, dysmenorrhea).

We appreciate the positive feedback on this manuscript. Pain assessment in women with PCOS is of paramount interest and because of a gap in this research area, we are trying to address it.

Weaknesses:

(1) Although the paper has strengths in methodology and data analysis, it also has some weaknesses.

The lack of a hypothesis doesn't allow us to evaluate the aim and significance of this study.

We would like to thank the Reviewer for their valuable feedback regarding the hypothesis of this study. We understand that the hypothesis may not have been written clearly under the objectives and we will correct this in the formal revision.

The primary hypothesis of this study is that women with PCOS experience a higher prevalence to pain (including dysmenorrhea, abdominal pain and pelvic pain) compared to women without PCOS, and this prevalence varies by racial groups. Our hypothesis aims to explore the relationship between PCOS and pain, the associated health risks, and the potential racial disparities in pain prevalence and long-term health outcomes. Additionally, we seek to assess the effect of treatment on reducing pain symptoms in women with PCOS. This study not only examines the immediate burden of pain but also investigates its long-term consequences, including risks of infertility, obesity, and type 2 diabetes.

To enhance clarity for readers, we will explicitly state this hypothesis in the revised manuscript and ensure that its connection to the study’s objectives is clearly articulated. We appreciate the Reviewer’s insights and will incorporate these refinements to strengthen the manuscript.

(2) The exclusion criteria don't include conditions, that can lead to symptoms similar to PCOS: thyroid diseases, hyperprolactinemia, and congenital adrenal hyperplasia. Thyroid status is not being taken into account in the criteria for matching. All these conditions could occur as on prevalence results as on risk assessment.

We would like to thank the Reviewer for highlighting the need to include these additional conditions that mimic PCOS. After excluding hypothyroidism, hyperprolactinemia, and adrenal hyperplasia from the PCOS and PCOS and pain cohorts, we observed that 7,690 patients (1.65%) with PCOS and 1,854 patients (1.36%) with PCOS were removed. Based on this observation, we plan to add these three conditions to our exclusion criteria and rerun our analysis for disease prevalence and relative risk for our resubmission.

We will update the manuscript accordingly to reflect these exclusions and ensure clarity in our methodology. Additionally, we will discuss the rationale for excluding these conditions to improve transparency and provide a more precise interpretation of our findings.

(3) The significant weakness of the study is the absence of a Latin American cohort. Probably the White cohort includes Latin Americans or others, but the results of the study cannot be extrapolated to particular White ethnicities.

We appreciate the Reviewer’s suggestion to include Latin American cohorts in studies. In this paper we only used race as a variable and did not incorporate ethnicity. However, for our resubmission we plan to include self-reported ethnicity in our analysis which will capture the Latin American cohort stratified by self-reported race groups. This addition will provide a more comprehensive understanding of racial and ethnic differences in our study population, and we will update the manuscript accordingly to reflect this expansion.

(4) The authors didn't provide sufficient rationale for future health outcomes and this list didn't include diseases of the digestive system or disorders of thyroid glands, which can also cause abdominal pain.

We appreciate the Reviewer comment and understand their concern. Our current results highlight the prevalence of disorders of the digestive system in Figure 2 and in the results section. To further strengthen our analysis, we plan to include disorders of the digestive system in our relative risk (RR) assessment. However, we will not be able to include the same analysis for thyroid dysfunctions as they will be considered as an exclusion criterion. These updates will be incorporated into the revised manuscript to ensure clarity and completeness.

Reviewer #2 (Public review):

Summary:

The study offers a thorough analysis of the prevalence of pain in women with polycystic ovary syndrome (PCOS) and its associations with health outcomes across various racial groups. Furthermore, the research investigates the prevalence of PCOS and pain among different racial demographics, as well as the increased risk of developing various conditions in comparison to individuals who have PCOS alone.

Strengths:

The study emphasizes pain as a significant comorbidity of PCOS, an area that is critically underexplored in existing literature. The findings regarding the increased prevalence of some of the diseases in the PCOS + pain group provide valuable direction for future research and clinical care. I believe physicians should incorporate pain score assessments into their clinical practice to improve patient's quality of life and raise awareness about pain management. If future research focuses on the mechanisms of pain, it would provide a better understanding of pain and allow for a focus on the underlying causes rather than just symptomatic management. The study also highlights the association between PCOS+pain and various comorbidities, such as obesity, hypertension, and type 2 diabetes, as well as conditions like infertility and ovarian cysts, offering a holistic view of the burden of PCOS.

We sincerely appreciate the Reviewer’s insightful comments. We hope that our findings will encourage further research on the occurrence of pain in women with PCOS and that others will replicate our results to strengthen the evidence in this area. As noted in our introduction, there are currently no standardized abdominal pain score assessments specifically for women with PCOS. We hope that the findings from this study will contribute to efforts toward developing a standardized pain assessment for the PCOS community. In the meantime, further research across more diverse populations will be essential to build a more comprehensive understanding of this issue.

Weaknesses:

Due to the nature of the retrospective study, some data may not be readily available in the system. Instead of simply categorizing participants based on whether they experience pain, it would be more useful to employ a pain scale or questionnaire to better understand the severity and type of patients' pain. This approach would allow for a more thorough analysis of pain improvement following treatment with the three widely used medications for PCOS. Additionally, it would be beneficial for the authors to specify subtypes of the disease rather than generalizing conditions, such as mentioning specific digestive system disorders or mental health disorders. The lack of detailed analysis of specific disorders limits the depth of the findings. This may cause authors to make incorrect conclusions.

We appreciate the Reviewer for highlighting the importance of categorizing pain levels experienced by women with PCOS. However, there is currently no standardized pain assessment for abdominal pain, and therefore more research is required before such a classification can be made. Additionally, the electronic health record data we leveraged via the TriNextX platform does not include any pain scale data from unstructured notes. Despite these limitations, this study is an important step toward recognizing abdominal and pelvic pain in women with PCOS. Our findings indicate that women with PCOS report abdominal pain independent of digestive conditions such as irritable bowel syndrome— a condition often associated with pain in this population.

We would like to thank the Reviewer for their thoughtful comment with respect to subtyping the future health outcomes. To address this, we plan to include the most common diseases associated with PCOS for each general disease group as a supplemental figure in the revised manuscript.