Title: Beyond Pelvic Pathology: Retinal Microvascular Rarefaction as a Systemic Marker in
Endometriosis
Version: 2 Date: 13 Jun 2025
Reviewer's report:
Major Issues
1. Overstatement of conclusions beyond data support
The authors repeatedly propose, in the abstract, discussion, and conclusion, that OCTA
parameters “may serve as surrogate markers for systemic vascular burden.” However, this is a
cross-sectional study, which does not allow for inference of causality. Moreover, no systemic
inflammatory or vascular biomarkers (e.g. VEGF, CRP) were measured, and no correlation
was drawn between OCTA parameters and disease severity or staging. At best, the current
data indicate a group difference, which is far from sufficient to support claims of predictive or
surrogate marker value. The conclusions should be revised to align strictly with the observed
findings.
2. Insufficient justification of the research hypothesis
Although using the retina as a window into systemic disease is an interesting concept, the
rationale for selecting the retina as a target organ in endometriosis is not well developed.
The underlying logic appears to be a general extrapolation: "Endometriosis affects systemic
microcirculation # the retina contains microvasculature # retinal vasculature might be affected #
therefore OCTA is relevant." This reasoning lacks specificity and scientific depth. Furthermore,
the potential clinical or scientific utility of retinal imaging in this disease remains unclear. The
authors are encouraged to more clearly define the rationale and potential implications of their
hypothesis.
3. Logical leaps and mechanistic speculation in the discussion
The discussion includes speculative mechanisms (e.g. VEGF, hormonal effects, angiogenic
sink) without any supporting biomarker or molecular data. Deductions based solely on vascular
density changes are logically incomplete. For example, the sentence “observed changes are
subclinical and secondary to systemic involvement” contains multiple unverified assumptions.
A more cautious phrasing would be preferable, such as:
“These subclinical microvascular changes may reflect early signs of systemic vascular
involvement, although no mechanistic data are currently available to support this hypothesis.”
4. Inadequate control of confounding variables
The authors do not report whether participants were receiving hormonal therapy, which could
significantly affect vascular parameters. While the authors controlled for menstrual cycle phase,
pharmacologic hormonal interventions (e.g. GnRH agonists, progestins, oral contraceptives)
may still bias the results. In addition, disease staging (e.g. rASRM classification) was not
considered, which may influence vascular burden. These omissions should be addressed in the
revision or clearly acknowledged in the limitations.
5. Unclear study positioning and limited clinical relevance
The study seems to straddle both mechanistic exploration and clinical application, yet the current
data do not support either path robustly. Although OCTA detected differences in parameters
such as VAD and FD-300, the authors have not provided a convincing rationale for clinical
relevance, such as screening, treatment monitoring, or risk stratification. The manuscript would
benefit from clearer positioning as a descriptive, exploratory study to avoid overextension of
its implications.
6. Insufficient data interpretation and mismatch between statistical support and discussion
Although the statistical results are clearly presented, the interpretation and scientific reasoning
in the discussion section are insufficient and not adequately grounded in the actual data. Several
issues should be addressed:
(1) Lack of detailed interpretation of specific parameters:
The manuscript presents group differences in multiple OCTA parameters, but the discussion
lacks item-by-item interpretation. For instance:
– Changes in parafoveal VAD vary across quadrants (e.g. inferior vs. nasal), but the authors do
not address this heterogeneity.
– FAZ area and circularity index show no significant differences, which potentially contradicts
the proposed hypothesis of vascular remodeling, yet are not discussed.
– FD-300 values show varying degrees of change across layers, but this is not explored.
(2) No statistical modeling or adjustment for potential confounders:
The analysis is limited to group comparisons using t-tests or Mann-Whitney U tests. There is no
multivariate regression or ANCOVA performed to adjust for key covariates (e.g. age, refractive
error, corneal thickness).
Additionally, it is unclear whether multiple comparisons correction (e.g. Bonferroni or FDR)
was applied, which increases the risk of false-positive findings when numerous OCTA variables
are tested simultaneously.
(3) Overlooked distributional differences and variability within groups:
While the two groups had similar mean ages (both 36 years), the standard deviation in the
endometriosis group (±8 years) is twice that of the control group (±4 years). This suggests
potential heterogeneity in hormonal or vascular status (e.g., approaching perimenopause) within
the endometriosis group. Relying solely on p-values and group means without accounting for
this variability may not be sufficient to rule out age-related confounding.
(4) Mechanistic speculations are not directly supported by data:
The authors speculate about increased VEGF, estrogen resistance, or vascular tone
abnormalities, but no systemic biomarker data (e.g. inflammatory markers or hormonal levels)
were collected. The current discussion relies heavily on literature-based assumptions without
a direct connection to the presented dataset. These hypotheses should be clearly identified as
speculative and separated from the actual findings.