Title: Polycystic ovary syndrome is associated with a higher risk of premalignant and malignant
endometrial polyps in premenopausal women: A retrospective study in a tertiary teaching
hospital
Version: 0 Date: 08 Jan 2023
Reviewer:  Stefano Palomba
Reviewer's report:
Title: Polycystic ovary syndrome is associated with a higher risk of premalignant and malignant
endometrial polyps in premenopausal women
Authors: Lu et al.
General comments
The current is a retrospective review of 4236 premenopausal women who underwent
hysteroscopic polypectomies aimed to evaluate the association between premalignant/malignant
polyps and the PCOS diagnosis.  PCOS resulted closely associated with premalignant
and malignant endometrial polyps in premenopausal women after adjustment for potential
confounding factors.
The study is very interesting and novel. I have suggested some changes to improve the paper.
Specific comments
Title
In the title should be specified the study design (and probably the sample size)
Abstract
The background should be changed and should be regard the PCOS and its potential cofactors
for endometrial disease.
The conclusions should be mitigated because the clinical risk is still very low. In addition, it is
possible that the PCOS status is not known, and it is not possible to suggest a complete evaluation
of the PCOS features in case of endometrial polyps.
Introduction
I suggest to introduce PCOS using well selected references. For example, for the diagnosis of
PCOS report specific criteria (doi: 10.1016/j.fertnstert.2018.05.004).
Please avoid generic comments on PCOS and focus your interest on endometrium. Recent data
suggest that endometrium (and not the oocyte, see doi: 10.1016/j.tem.2016.11.008) is a crucial
component for the reduced fecundity (doi: 10.1093/humrep/deab181) and for the increased risk
of pregnancy complications (doi: 10.1093/humupd/dmv029) in women with PCOS.
The paragraph “Moreover, a considerable proportion of endometrial polyps are asymptomatic
and are found incidentally by transvaginal ultrasonography in premenopausal women during
their routine health check-ups or in the diagnosis of other gynaecological diseases. Therefore,
it is necessary to investigate the prevalence of (pre)malignant endometrial polyps and their
association with PCOS in premenopausal women.” Is not useful for introducing the study aim.
I suggest to discuss about the potential need to change the common clinical practice in presence
of PCOS diagnosis for a potentially higher risk of premalignant lesion.
The study aim should be changed and simplified in “the aim of the current study was to clarify
if the PCOS diagnosis is associated to increased risk of premalignant and malignant polyps in
premenopausal women”. Avoid other comments.
Methods
One methodological error could be that, at the study design, a correct and proven PCOS diagnosis
was not considered as inclusion criteria for the cases. In other words, patients with unclear PCOS
diagnosis should be included in the non-PCOS group in order to maintain the large size of the
study. On the contrary, it is possible to select only patients with proven PCOS diagnosis (cases)
and only patients with exclusion PCOS diagnosis, normal menstrual cycles without clinical
hyperandrogenism (at least) and normal USG (controls).
Please clarify the term “premalignant”.
Please clarify the definition of obesity in your population.
PCOS diagnosis was performed using Rotterdam criteria. Because it was a retrospective
analysis, were considered the historical data (PCOS in the anamnesis) or have you analyzed the
clinical and biochemical data (to have a PCOS diagnosis)? Please read and cite this paper to
understand the sense of the analysis (doi: 10.1038/nrendo.2013.248)
Results
I suggest avoiding subsections.
The use of the word “(pre)malignant” is confusing.
The authors should better clarify their histologic findings. For the Reviewer, it is not clear the
cases of malignant and premalignant lesions on polyps or on endometrial biopsies or both. In
the Methods section they included patient with endometrial polyps; however, it is needed to
know how much patients had really a polypectomy or an endometrial biopsy or both. This point
is crucial.
The authors performed data sub-analyses but they did not analyzed the obtained finding for
PCOS phenotypes. I suggest showing your data detailing the PCOS phenotypes observed in your
populations (you could also include a group with “unclassified PCOS phenotypes”) and the data
analysis (risk of premalignancy and malignancy) according to each PCOS phenotype. I could
also be useful to know the weight for each PCOS feature in terms of risk.
Discussion
The prevalence of premalignant and malignant lesions is not low. Anthropometric characteristics
are fundamental.
The discussion should follow the new findings requested on PCOS phenotypes and features.
Figure and Tables
The figures and tables should be revised according to the suggestions made. For example,
the figure 2 is unclear. The histologic findings regard endometrial biopsies performed during
polypectomy or what? The term “endometrial polyps” is not clear: without atypia? What?
References
I suggest reading and citing the current comprehensive review (doi: 10.1093/humupd/dmaa051)
that may give you inputs for optimize the introduction and discussion, the reference (Giudice,
Best Pract Res Clin Endocrinol Metab. 2006) may be replaced.
Please include ref. for Rotterdam criteria and WHO classification for histologic diagnosis.