Reviewer’s report
Title: 
Does Endometriosis Increase Susceptibility to COVID–19 Infections? A
case-control study in Women of Reproductive Age
Version: 
1 
Date: 
22 Nov 2020
Reviewer's report:
The study should be better justified and references should be support the reason
to research the susceptibility of COVID -19 in endometriosis patients, for
example, if it would be in relation to ACE2, or if it would be in relation to other
aspects of the immune system. In this study, the justification was not clear. 
In addition, the study should be conducted with a larger number of patients,
aiming a better statistical result, and it could be conducted with a more
homogeneous group, with less bias.
In relation to Background - the study starts by contextualizing the COVID -19
and its relation with the ACE2 expression - lines 52 to 67. However, when
describing the relationship of ACE2 with the female reproductive system, it is
not done in a clear and adequate way. Initially in lines 68-69, it is mentioned that
the ACE2 protein is related with the testicles, ovaries and fertility processes. But
what is the effect on physiology and pathology, is it an important role? 
In the sequence lines 70-71, reference 10 is cited, where the relationship between
COVID-19 and male gametogenesis. However, the question is what about the
female gametogenesis? What would be the impact of COVID-19?
It follows the description of the relation between COVID-19 and endometrial
infection, and the description of ACE2 expression in the endometrium. After
that, the presence of ACE2 and endometrial cancer. However, the study is about
endometriosis, and there is no reference about the expression of ACE2 in
endometriosis lesions. 
Then, there is the description of endometriosis in lines 80-82. After that, on lines
82-83, the relation of endometriosis with alterations in the immune system is
mentioned, but what are these relations? And what relation could there be with
COVID-19? It is not clear on the text.
Next, on lines 83-85, the sentence is not supported by the reference.
At the end of background, there is no justification for the study. There are not
clear evidences about why endometriosis could increase the susceptibility to
COVID-19. 
Regarding the methodology, the number of 500 patients in each group was based
on the prevalence of 13% of the population (data presented in the study by
Signorelli), but in this study it was reported that the prevalence of COVID-19
varied from 0.35-13%, being 13% only in the region of Lombardy, while the
prevalence of Italy in general was 4%. 
The 4% of prevalence was found in each group of women in this study. The
study found in each group 3.2% of women with COVID-19 in the case group
and 3% in the control group, and that is so different from the 13% that was used
to base the sample size. 
In the 500 women group, they found just 16 patients in each group with COVID-
19, a small number to study the susceptibility of COVID-19 in endometriosis
patients. The study should be conducted with more women for a better statistical
result. 
In addition, the study presents an important bias, the women in the control group
have many comorbidities. And they should use concomitant medications, which
could have an impact on the difference in symptoms found in both groups. Thus,
the study should be conducted with more homogeneous groups. 
After the Discussion, in lines 171-186, it is described the relation that COVID-
19 can have in endometrial cells and in endometrial cancer, and other types of
cancer that can also increase the susceptibility to COVID-19 are cited. However,
this study is about endometriosis and it is not about endometrial cancer. 
The physiopathology of endometrial cancer differs from endometriosis, so what
is the relationship between endometrial cancer, COVID-19 and endometriosis?
After the lines 186-196, the description of the physiopathology of endometriosis
with immune system begins. However, in the following lines 192-194, changes
in the immune system are correlated with increased ACE2 expression, and the
susceptibility of SARS-COv2 with endometrial cancer. The authors should
search for references to support the relationship between ACE2 and
endometriosis.
After that, in lines 194-198, authors justify that an increase in the susceptibility
to COVID-19 in endometriosis patients was not found, because endometriosis is
a chronic inflammatory disease while COVID- 19 is acute. This was an early
statement made, without any justification or support in the literature. 
On lines 199-204, there is a description of the relationship between the
differences in symptoms of each group, but it is important to highlight that
besides the groups are small, they are different in terms of comorbidities, which
can be the confounding factor in terms of symptoms, what is said after lines 233-
235.
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Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
No
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes