Review Reports - Feasibility of Targeted Case-Finding of Polyendocrine Metabolic Ovarian Syndrome in the Workplace: A Pilot Cohort Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Major Comments

The study population and selection process require clearer definition

The manuscript reports that 2,085 employees were invited to participate, with a participation rate of 91.7%, and that the study included 1,170 women, of whom 767 were women of reproductive age. However, the manuscript should provide a clearer description of the study population, including the occupations represented; relevant socioeconomic characteristics; the age distribution of the 767 women of reproductive age; the operational definition of “reproductive age”; and whether pregnancy, hormonal contraception, hysterectomy, or other reproductive conditions constituted exclusion criteria.

It should also be clarified whether occupational health physicians received standardized training in conducting the relevant clinical interviews.

The term “screening” should be reconsidered

The main concern is that the study did not screen all women of reproductive age for PMOS. Instead, an in-depth interview was conducted only among women selected on the basis of suspected eating disorders, borderline EDE-QS scores, overweight/obesity, metabolic abnormalities, sleep problems, or mental health concerns.

This approach introduces substantial selection bias and means that the reported figure of 2.7% cannot be interpreted as the prevalence of newly diagnosed PMOS in the workplace population. The authors themselves acknowledge that the selection of women within the nutritional/metabolic health-promotion program excluded women without these characteristics and that screening all women of reproductive age would likely have identified additional cases.

The authors should therefore revise the title, abstract, Discussion, and Conclusions so that the study is consistently presented as a pilot targeted case-finding/feasibility study, unless a stronger justification can be provided for the use of the term “screening.”

A possible alternative title would be: “Feasibility of Targeted Case Finding for Polycystic Ovary Syndrome During Occupational Health Examinations: A Pilot Cohort Study”

If the authors retain the term “screening,” they should explicitly define what they mean by screening and explain why the targeted strategy employed in this study meets that definition.

The PMOS diagnostic procedure requires substantially greater detail

The manuscript describes a structured interview based on the Pedersen and Kalra questionnaires, followed by referral for ultrasonography, AMH measurement, and endocrinological and gynecological consultation. However, several important methodological details are missing, including:

the scoring algorithm;
the prespecified threshold for clinical suspicion;
inter-rater reliability;
test–retest reliability.

The manuscript also does not provide sufficient information regarding how the final diagnosis was established in each of the 21 confirmed cases.

The authors should specify:

which diagnostic criteria were applied;
whether the 2023 International Evidence-based Guideline criteria were used;
which two diagnostic domains were fulfilled by each patient;
how alternative diagnoses were excluded;
whether biochemical hyperandrogenism was assessed;
whether ovarian morphology was assessed by ultrasound;
how AMH was incorporated into the diagnostic process;
whether the final diagnosis was established by a gynecologist and/or endocrinologist;

This issue is particularly important because the manuscript appropriately states that the definitive diagnosis should be reserved for specialists. The diagnostic pathway should therefore be documented in sufficient detail to allow readers to assess the validity and reproducibility of the case ascertainment process.

The reported “prevalence” of 2.7% may be misleading

The manuscript states that 21 female employees were diagnosed with PMOS and reports a prevalence of 2.7% (95% CI, 1.7–4.2). Numerically, 21/767 is approximately 2.7%; however, this does not represent the prevalence of PMOS in the underlying population because the diagnostic interview was performed only in a selected subgroup.

A more appropriate interpretation appears to be the proportion of newly identified/confirmed cases among the 767 women of reproductive age included in the cohort, rather than the prevalence of PMOS.

Furthermore, seven of the 28 women with an initial clinical suspicion did not appear among the 21 subsequently confirmed cases. The manuscript should clarify the status of these seven women. Specifically, it should be stated whether they:

underwent diagnostic evaluation and were ultimately found not to have PMOS;
did not complete the diagnostic assessment;
could not be contacted;
declined further evaluation; or
had an unresolved or indeterminate diagnostic status.

This information is essential for evaluating the completeness of case ascertainment and the validity of the reported diagnostic yield.

The statistical analysis is insufficient for the small number of confirmed cases

Only 21 women had confirmed PMOS. Nevertheless, the manuscript reports multiple comparisons involving BMI, glycemia, cholesterol levels, sleep quality, anxiety, depression, and eating-disorder-related outcomes.

With such a small number of confirmed cases, the resulting estimates are likely to be highly unstable, while the risk of type I error arising from multiple comparisons is substantial.

The manuscript should therefore:

report the exact sample size for each statistical comparison;
provide effect estimates and 95% confidence intervals rather than relying primarily on p-values;
state whether the assumptions underlying the parametric tests were assessed and met;
clarify which variables were analyzed using t-tests and which using Mann–Whitney U tests;
consider whether an appropriate adjustment for multiple testing is warranted; and
avoid implying that statistically significant associations establish clinically meaningful or causal relationships.

Given the pilot nature of the study and the small number of confirmed cases, the statistical analyses would be more appropriately framed as exploratory and hypothesis-generating.

The Discussion contains several statements that extend beyond the evidence provided by this pilot study

The Discussion includes statements suggesting that identification of PMOS may improve quality of life, work ability, and economic outcomes, and these claims are used in part to justify screening in the workplace.

While such potential benefits are plausible and clinically relevant, they were not directly evaluated in the present study. The wording should therefore be moderated and clearly distinguished from findings demonstrated by the current investigation. Such outcomes may be presented as potential implications or hypotheses for future research rather than as established consequences of PMOS case identification.

Minor Comments

Terminology: The manuscript uses the terms PCOS and PMOS interchangeably. Because the proposed change in terminology is relatively recent, the authors should clearly define when the term “PCOS” is used in accordance with the historical literature and when “PMOS” is used as the preferred contemporary terminology.

The abstract should clearly state that participants were selected on the basis of nutritional, metabolic, sleep, or mental health-related characteristics rather than through universal screening of all women of reproductive age.

Prevalence: The phrase “prevalence of newly diagnosed PMOS” should be replaced with a more precise expression, such as “proportion of newly identified cases among women of reproductive age,” unless the authors provide a convincing justification for the current terminology.

Predictive value: The term “predictive value” should be replaced with “confirmation rate” unless complete diagnostic verification of all 28 clinically suspected cases can be documented.

References and manuscript metadata: The reference list should be carefully checked for consistency, DOI formatting, journal abbreviations.

Author Response

Reviewer #1

Major Comments

The study population and selection process require clearer definition

It should also be clarified whether occupational health physicians received standardized training in conducting the relevant clinical interviews.

Response: I feel compelled to thank the reviewer for providing very useful suggestions for substantially improving the work. I believe reviewing is a very important part of the publication process, and I know it takes a lot of time. Therefore, I thank him/her for his/her time and professionalism.

The opportunity to participate in the health promotion activity was offered to all workers who underwent a medical examination in 2022. They belonged to 42 companies, primarily small (fewer than 50 employees) or micro-businesses (fewer than 10 employees) that represent 99% of active companies in Italy. Workers performed a wide variety of tasks with varying degrees of responsibility. Occupational hazards included biological agents, manual handling of loads, night work, ionizing and non-ionizing radiation, work with video terminals, and numerous others. I grouped them into four production sectors to avoid excessive fragmentation. I have added this data to the description.

Thank you for pointing out that I did not include the average age of fertile women; I have added this information. As requested, I specified the definition of childbearing age, indicating that these women were still menstruating, even if sometimes they were over the age of 44 indicated by the Centers for Disease Control and Prevention as reproductive age.

The medical examinations and interviews were conducted by a single physician, the author of the article, a specialist in occupational medicine with no specific knowledge of this condition. Therefore, the diagnosis and treatment were entrusted to specialists from the national health service, and the occupational physician merely initiated the procedure and recorded the outcome a year later. This indicates that the procedure whose feasibility this article aims to test can be applied by any doctor in other companies. This clarification has been added to the manuscript.

Based on the nutrition survey, women who had problems likely associated with PMOS were selected for interviews. The only criterion for excluding women from the interview was menopause, whether natural or iatrogenic. Use of oral contraceptives was systematically assessed during periodic visits, as was reproductive history. These conditions were discussed in the in-depth interviews. I explained all this in the manuscript.

The methods section now reads as follows:

2.1. Population

Workers who were monitored by the Catholic University of the Sacred Heart of Rome, Italy, in 2022 were invited to participate in a health promotion program that included screening for eating disorders (EDs). They belonged to 42 companies, primarily small (fewer than 50 employees) or micro-businesses (fewer than 10 employees) that represent 99% of active companies in Italy. Workers performed a wide variety of tasks with varying degrees of responsibility. Occupational hazards included biological agents, manual handling of loads, night work, ionizing and non-ionizing radiation, work with video terminals, and numerous others. 91.7% of the 2,085 workers agreed to participate. Of these, 1,170 were female; their age ranged from 22 to 70 years (mean 44.6±11.7 years), and 767 (65.6%, mean age 37.3 ± 7.9 years) were in childbearing age, that is, they were still menstruating, even if sometimes they were over the age of 44 indicated by the Centers for Disease Control and Prevention as reproductive age. The results of the cross-sectional population-based project have been published [52-54]. The survey allowed us to identify the female workers who were most likely to be suspected PMOS and invite them for an in-depth interview. The interview identified those women of childbearing age suspected of having PMOS and followed them for one year, until the next periodic medical examination. The cohort study followed the STROBE guidelines [55] (Table S1).

The term “screening” should be reconsidered

A possible alternative title would be: “Feasibility of Targeted Case Finding for Polycystic Ovary Syndrome During Occupational Health Examinations: A Pilot Cohort Study”

If the authors retain the term “screening,” they should explicitly define what they mean by screening and explain why the targeted strategy employed in this study meets that definition.

Response: I thank the reviewer for suggesting a title that more accurately reflects the activity performed than the term "screening." In fact, the in-depth interview was focused on the workers most likely to have suspected PMOS. This was done to limit the time and refine the method. Case selection was essential to avoid extending in-office visits, which can be incompatible with companies' production needs. I am convinced that there could have been other cases in the population who were not interviewed because they did not fall into the risk groups. I have modified the title, abstract, discussion, and conclusions according to this concept. I tried to better explain the method and clarify that 2.7% is the percentage of newly confirmed cases among women of childbearing age, not the prevalence of PMOS in the cohort. The term "screening" in the article remained only in reference to the survey on eating disorders, which involved all male and female workers before or after menopause.

The title of the manuscript now is: Feasibility of targeted case-finding of Polyendocrine Metabolic Ovarian Syndrome in the workplace. A pilot cohort study.

The Abstract now reads as follows:

Polyendocrine Metabolic Ovarian Syndrome (PMOS) is the most common endocrine disorder in working women. Workplace screening could contribute to the early diagnosis and treatment of this chronic condition. Fertile women who participated in a 2022 health food promotion campaign and had suspected eating disorders, overweight/obesity, metabolic abnormalities, sleep problems, or mental health concerns were interviewed about PMOS symptoms during their in-office medical examination. 28 of the 1,170 women examined had symptoms of suspected PMOS. By 2023, 21 of these diagnoses had been confirmed by specialists. The prevalence of newly diagnosed PMOS among the women of childbearing age was 2.7% (CI95% 1.7; 4.2). The confirmation rate of the clinical suspicion of PMOS was 75% (CI95% 55.1; 89.3). Female workers with newly identified PMOS had a significantly higher frequency of eating disorders than their pre-menopausal colleagues; higher body mass index values), higher glycemia and higher cholesterol values. PMOS patients also had higher depression symptom scores than other workers of childbearing age. In conclusion, with a short interview during mandatory medical examinations, the occupational physician can make a significant contribution to the diagnosis of PMOS, thereby hopefully improving the quality of life of women and reducing damage to their health.

The PMOS diagnostic procedure requires substantially greater detail

the scoring algorithm;
the prespecified threshold for clinical suspicion;
inter-rater reliability;
test–retest reliability.

The manuscript also does not provide sufficient information regarding how the final diagnosis was established in each of the 21 confirmed cases.

The authors should specify:

which diagnostic criteria were applied;
whether the 2023 International Evidence-based Guideline criteria were used;
which two diagnostic domains were fulfilled by each patient;
how alternative diagnoses were excluded;
whether biochemical hyperandrogenism was assessed;
whether ovarian morphology was assessed by ultrasound;
how AMH was incorporated into the diagnostic process;
whether the final diagnosis was established by a gynecologist and/or endocrinologist;

Response: I completely agree with the reviewer that more information is needed to better understand the type of activity carried out in the workplace.

The medical examinations were performed by a single doctor, once for each worker, in 2022 and 2023; consequently, it was not possible to evaluate the inter-observer reliability and the test-retest reliability. However, the questionnaires that guided the interviews had been validated by the authors, who had proposed them as self-completed screening tools.

The occupational physician, who is not a specialist in this condition, formulated suspicion based on the Rotterdam International Criteria. The criterion for suspicion was the presence of clinical signs of both ovulatory dysfunction and hyperandrogenism. In the workplace it was not possible to carry out tests for biochemical hyperandrogenism (total testosterone, free testosterone, androstenedione, DHEAS), nor ovarian ultrasound or AMH, therefore the workers were invited to contact the National Health Service facilities and their trusted specialist.

Following the occupational physician's instructions, each of the women chose their own diagnostic and therapeutic path. Each of them followed the instructions of their doctors. The occupational physician verified the confirmation of diagnosis one year later. All these concepts have been detailed in the methods section and discussion, and in the section on the limitations.

The 2^nd part of section 2.3 now reads as follows:

The Pedersen and Kalra questionnaires were used as a framework for the interview between the occupational physician and the worker. The conversation developed differently on a case-by-case basis, considering the elements of each woman's individual history, such as reproductive history, use of drugs and hormone treatments, surgical procedures. No algorithm was applied, as would have been necessary for a self-completion questionnaire. At the end of the interview and medical examination, the doctor was able to formulate an eventual clinical suspicion of PMOS. The criterion for suspicion was the presence of clinical signs of both ovulatory dysfunction and hyperandrogenism. Female workers who exhibited symptoms consistent with a diagnosis of PMOS were advised to contact their general practitioner for further testing through the National Health Service (NHS). During the subsequent medical examination at the workplace, they were questioned about the results of the diagnostic and therapeutic process. All workers were examined for the first time in 2022 and a second time in 2023.

The 2^nd part of results now reads as:

During medical examinations conducted at the workplace after interviews, 28 women were suspected of having PMOS, as they reported symptoms of hyperandrogenism and ovulatory irregularities. Of these workers, 14 had suspected EDs and associated metabolic disorders; the others had endocrinological problems, overweight, alterations in the menstrual cycle and dermatological problems. They were sent by their general practitioners for further specialist tests, including ovarian ultrasonography, anti-Müllerian hormone (AMH) dosage, hormonal testing, endocrinological and gynecological consultancy, to confirm or exclude the diagnosis.

At the subsequent periodic examination, 21 workers reported having been diagnosed by a gynecologist and/or endocrinologist with PMOS (proportion of newly identified cases among women of childbearing age 2.7%, CI95% 1.7; 4.2). The suspect diagnosis was confirmed by specialists in 75% of cases (CI95% 55.1; 89.3). The women were under dietary control and had increased physical activity. They also followed the treatments suggested by their attending physicians to control metabolic and mental health comorbidities. Of the seven cases for which the suspicion of PMOS was not confirmed in the 2023 visit, one declined further diagnostic evaluation because had gone into menopause, two had ceased employment and had not completed the diagnostic assessment, and four were found not to have PMOS by their physicians.

Female workers with a confirmed diagnosis of PMOS had significantly higher EDE-QS scores than their pre-menopausal colleagues (14.6±8.2 vs. 4.6±4.7, Student’s t p<0.001; Mann-Whitney U p<0.001). The effect size was large (Cohen’s d = -2.09; 95%CI -2.54; -1.65). The newly confirmed cases had higher BMI mean values (26.9±5.2 vs. 23.3±4.3; Student’s t p<0.001; Cohen’s d = -0.84; 95%CI -1.32; -0.35) than other fertile women. They also had higher glycemia (120.5±49.3 vs. 81.7±25.2, Student’s t p<0.001; Cohen’s d = -1.46; 95%CI -2.10; -0.81) and higher cholesterol values (232.7±24.5 vs. 181.6±37.7, p<0.001; Cohen’s d = -1.36; 95%CI -2.04; -0.686) than their colleagues. Confirmed PMOS patients also had lower sleep quality scores (PSQI score 7.6±5.0 vs. 5.6±3.1, Student’s t p=0.005; Cohen’s d = -0.62; 95%CI -1.06; -0.19; Mann-Whitney U p=0.75) and higher anxiety scores (4.1±3.3 vs. 2.8±2.6, Student’s t p=0.019; Cohen’s d = -0.518; 95%CI -0.952; -0.083; Mann-Whitney U p=0.073) but the effect size of the difference was not large and the nonparametric tests approximated significance without reaching it. Newly diagnosed PMOS cases had higher depression symptom scores (3.3±2.6 vs. 1.7±2.1, Student’s t p<0.001; Cohen’s d =-0.78; 95%CI -1.22; 0.348; Mann-Whitney U p=0.004) than other workers of childbearing age.

The 1^st part of Discussion:

Developed as an addition to a health food promotion program, this study demonstrated the feasibility of targeted case-finding of PMOS in the workplace. Medical interviews conducted on women who had eating disorders, obesity or metabolic disorders detected suspected cases of PMOS which were confirmed by subsequent instrumental and laboratory tests in 75% of cases. The high positive confirmation rate of our clinical interviews appears to recommend extending the use of such structured interviews during workplace medical examinations to help detect undiagnosed cases.

The medical examinations and interviews were conducted by a single physician, the author of the article, a specialist in occupational medicine with no specific knowledge of this condition. Therefore, the confirmation of diagnosis and the treatment were entrusted to specialists from the national health service, and the occupational physician merely initiated the procedure and recorded the outcome a year later. This very simple procedure can be applied by any doctor in other companies.

The 2^nd part of limitations:

Thirdly, consideration must be given to the fact that both the selection of the workers and the judgement resulting from the in-depth interviews followed subjective and therefore fallible criteria. However, having started to deal with the problem has made it clear to the doctor and the workers that PMOS is a syndrome that should not be overlooked. Fourth, the occupational physician had no control over the diagnostic and therapeutic pathways followed by each suspected patient. However, the action taken in the workplace was useful in establishing a channel of communication with general practitioners, endocrinology and gynecology specialists chosen by each patient.

The reported “prevalence” of 2.7% may be misleading

A more appropriate interpretation appears to be the proportion of newly identified/confirmed cases among the 767 women of reproductive age included in the cohort, rather than the prevalence of PMOS.

underwent diagnostic evaluation and were ultimately found not to have PMOS;
did not complete the diagnostic assessment;
could not be contacted;
declined further evaluation; or
had an unresolved or indeterminate diagnostic status.

This information is essential for evaluating the completeness of case ascertainment and the validity of the reported diagnostic yield.

Response: As the reviewer correctly points out, 2.7% is not the prevalence of PMOS cases in the cohort, but only that of new cases discovered in this study among the women of childbearing age. We could hypothesize that there were other cases who were neither interviewed nor tested. I have explained these concepts more accurately.

Of the seven cases for which the suspicion of PMOS was not confirmed in the 2023 visit, one declined further diagnostic evaluation because had gone into menopause, two had ceased employment and had not completed the diagnostic assessment, and four were found not to have PMOS by their physicians. I added this information to the results.

The statistical analysis is insufficient for the small number of confirmed cases

With such a small number of confirmed cases, the resulting estimates are likely to be highly unstable, while the risk of type I error arising from multiple comparisons is substantial.

The manuscript should therefore:

report the exact sample size for each statistical comparison;
provide effect estimates and 95% confidence intervals rather than relying primarily on p-values;
state whether the assumptions underlying the parametric tests were assessed and met;
clarify which variables were analyzed using t-tests and which using Mann–Whitney U tests;
consider whether an appropriate adjustment for multiple testing is warranted; and
avoid implying that statistically significant associations establish clinically meaningful or causal relationships.

Given the pilot nature of the study and the small number of confirmed cases, the statistical analyses would be more appropriately framed as exploratory and hypothesis-generating.

Response. Following the reviewer's suggestion, I have reported the number of cases in Tables 1 and 2, and I have specified the statistical test used when it was not indicated. I completely agree that comparing the small group of confirmed cases with other workers can give unstable results, but above all, it is flawed by the fact that the interviews were conducted only with women with eating, metabolic, and neuropsychiatric problems. Therefore, some differences were expected. In the results, I tested the effect size of the comparisons between the small group of confirmed cases and the other workers, using Cohen's d an confidence intervals. In the discussion, I have more correctly framed the meaning of the observed differences, which also refer to a group that had been previously selected precisely for these parameters and were therefore expected. I have also modified the abstract in accordance with these observations.

In the manuscript, I attempted to avoid interpreting statistically significant associations as clinically significant or causal relationships. I specified that the comparisons between the small group of confirmed cases and the other workers were affected by the selection made before the interviews.

The Discussion contains several statements that extend beyond the evidence provided by this pilot study

Response: We fully agree with the reviewer. The consolidated evidence provided by the literature should not be confused with the results of this feasibility study. I have modified any sentence that might have given this impression, emphasizing the source of the statements. In the abstract, the improvement in health status and quality of life that can be achieved after diagnosis and treatment are referred to as "hopefully."

Minor Comments

Response: I agree. I used the new term (PMOS) in the manuscript, leaving the other term (PCOS) only when it was taken from a reference.

Response: I appreciated this request and, in addition to changing the title, I also changed the abstract.

Response: I agree, I have modified the manuscript accordingly.

Predictive value: The term “predictive value” should be replaced with “confirmation rate” unless complete diagnostic verification of all 28 clinically suspected cases can be documented.

Response. This is correct, I have modified the manuscript accordingly.

References and manuscript metadata: The reference list should be carefully checked for consistency, DOI formatting, journal abbreviations.

Response: Thanks to the reviewer's invitation, I carefully checked the references

Reviewer 2 Report

Comments and Suggestions for Authors

This well-written study screened women suspected of having polyendocrine metabolic ovarian syndrome (PMOS) in the workplace. Out of 1170 participants, 28 showed symptoms consistent with PMOS, and 21 were confirmed, resulting in a clinical suspicion predictive value of 75%. The study is significant because PMOS is a common condition among women, often impacting quality of life. A brief interview during mandatory medical exams could identify women with the condition who are unaware of it, enabling early treatment.

While the manuscript is well-conducted and appropriately discusses its strengths and limitations, I have a few comments.

Lines 285-288 mention AMH levels to confirm PCOS/PMOS diagnosis; however, although AMH is a helpful indicator of polycystic ovarian morphology, its use to confirm diagnosis could be problematic because there is no universal cutoff value, it varies significantly by age and assay type, and it is unreliable in adolescents. These limitations could be mentioned.

For all studies listed in the document (lines 412-425), include the sample size and, if available, the p-values. This helps the reader assess the significance of each study.

Keywords: The authors might consider adopting the new name for polycystic ovarian syndrome.

Author Response

Reviewer #2

Response: I sincerely thank the reviewer for the time he/she took to review the manuscript, for the helpful advice he/she gave and for the encouragement that comes from his/her appreciation.

While the manuscript is well-conducted and appropriately discusses its strengths and limitations, I have a few comments.

Response: I completely agree. The work performed by the occupational physician served to identify a clinical suspicion of PMOS, but the specialist diagnosis and confirmatory tests were entrusted to the National Health Service and the specialists chosen by each woman. The occupational physician initiated the diagnostic process but had no role in further diagnostic investigations and treatment. I reported this limitation.

For all studies listed in the document (lines 412-425), include the sample size and, if available, the p-values. This helps the reader assess the significance of each study.

Response: I agree. I expanded the section and added the data requested by the reviewer. This greater detail can help the reader to evaluate the reported references.

The section now reads as follows:

A few studies have examined the role of occupational factors in PMOS etiopathogenesis. A Chinese case-control study on 366 patients with PCOS and 325 controls associated the syndrome and insulin resistance with occupational stress levels by logistic regression models, obtaining a low cumulative determination coefficient (R²=0.22) [138]. Another Chinese study failed to observe a relationship between shift work and PCOS in a prospective cross-sectional study of 231 women, including healthcare workers recruited for an annual health screen. Nevertheless, women who indicated sleeping less than 6 hours were more prone to report irregular menstrual cycle durations (OR = 2.1; 95% CI, 1.1 to 4.2), elevated fasting insulin concentrations (mean difference = 2.13; 95% CI, 0.27 to 3.99 mU/L) and increased likelihood of insulin resistance (OR = 2.58; CI, 1.16 to 5.76) [139]. The limited number of studies in the workplace is compensated for by epidemiological investigations that link this pathology to environmental factors. For example, a Chinese case-control study on 169 patients and 338 matched controls observed an association between PCOS and certain habits such as eating plastic-packaged food, eating contaminated fruit with pericarp and drinking alcohol [140]. Another Chinese retrospective case-control study on 108 cases and 108 controls, after multivariate analyses, associated using disposable plastic cups for drinking, being exposed to cooking oil fumes and to indoor decorations with the syndrome [141]. A more recent retrospective case-control study on 178 PCOS patients and 206 controls from a Chinese tertiary hospital reported an association of outdoor particulate air pollution with the syndrome [142]. On the contrary, a longitudinal register-based Danish cohort study including 21,619 residents during 380,000 person-years found no evidence of an association between environmental polychlorinated biphenyl pollution levels and incident PMOS cases [143]. A Swedish cohort study composed by 29,106 female who had resided in a municipality with perfluoroalkyl substances (PFAS)-contaminated water has demonstrated that exposure to high levels of PFAS in drinking water is associated with an increased risk of PCOS [144]. Endocrine disruptors and microplastics are among the factors most often associated with the disease [145-147]. Ecological studies suffer from an inevitable time lag between the release of new contaminants into the environment (e.g. micro- and nanoplastics, substitutes for bisphenol A and plasticizers, and flame retardants), and the availability of epidemiological data on populations [148]. Ecosystem pollution due to a complex set of endocrine disruptors appears to be the main cause of the global increase in PMOS.

Keywords: The authors might consider adopting the new name for polycystic ovarian syndrome.

Response: At the reviewer's request, I used the new term (PMOS) in the manuscript, leaving the other term (PCOS) only when it was taken from a reference. I removed the entry from the keywords.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I have no further comments.