Title: Exploring the Role of Negative Expectations and Emotions in Primary Dysmenorrhea:
Insights from a Case-Control Study
Version: 1 Date: 28 Jan 2025
Reviewer:  Marcelo De França Moreira
Reviewer's report:
The manuscript addresses the important and highly relevant theme of primary dysmenorrhea,
exploring the psychological and physiological mechanisms influencing menstrual pain.
However, significant methodological and conceptual shortcomings must be addressed before
the manuscript can be considered for publication. These include concerns regarding the validity
of how constructs were assessed, the lack of adequate diagnostic exclusion for secondary
dysmenorrhea, insufficient justification of sample size, limited control of confounding factors,
and the absence of multiple testing corrections. Addressing these issues is essential for the
manuscript to make a meaningful and reliable contribution to the field.
Abstract
• Revise the hypothesis in the abstract to avoid tautology, particularly the phrase "heightened
pain anticipation and negative emotions amplify menstrual pain." Suggest rephrasing to
specify interactions: "Cognitive-emotional factors such as heightened anticipation and negative
emotions intensify menstrual pain severity and associated functional disability in primary
dysmenorrhea."
• Clearly define key outcomes mentioned, such as "Participants with severe pain exhibited
significantly higher anticipatory stress scores compared to controls (mean difference: 50%, 95%
CI: X-X)." Specify these details where outcomes are briefly summarized.
Introduction
• Revise the statement, "But also cognitive factors, such as the expectation of pain, and associated
anticipatory anxiety, may play a role" (Page 2, Paragraph 3). Provide specific examples from
literature supporting the role of anticipatory cognitive-emotional mechanisms in nocebo-induced
hyperalgesia.
• The sentence "It is reasonable to assume that cyclic events like menstruation can also trigger
anticipatory negative emotions and cognitions, leading to expectation-induced exacerbation of
pain" (Page 2, Paragraph 3) lacks citations. Include references to support this claim.
• Replace "more sensitive to pain signals" with "nociceptors became sensitized." Nociception
refers strictly to the physiological detection of harmful stimuli, distinct from the subjective
experience of pain.
• Define what is meant by "anticipatory negative emotions" by explicitly identifying the
emotions explored in the study, such as anxiety, depression, or stress. Ensure consistent usage
of this terminology throughout the introduction.
• Specify the study’s hypothesis to ensure precision and avoid circular reasoning. For instance,
the statement "women with high menstrual pain would expect more intense menstrual pain" is
ambiguous. Does the hypothesis address progressive changes in pain anticipation over time, or
does it focus solely on baseline severity and emotional responses? Ensure that this distinction
aligns with the study’s stated objectives and clarifies unclear points.
• The phrase "Enhancing knowledge about the potential impact of negative expectations and
anticipatory anxiety on the severity of menstrual pain..." (Page 2, Paragraph 4) should be
elaborated to specify how this understanding contributes to clinical management.
Methods
• The authors state, "The sample size was defined a priori, without a formal sample size
calculation" (Page 6, Statistical Analysis). If arguing the exploratory nature of the study, they
should clarify that the sample size was not statistically determined and explain factors like
feasibility or resource constraints.
• Mention explicitly the challenges of collecting medical data remotely and outline how you
ensured accuracy. Were any validation checks or cross-references implemented for self-reported
information, such as menstrual cycle length or history of dysmenorrhea?
• Revise the pain thresholds used for categorizing participants (Page 4, Participant Eligibility).
Current criteria for "mild pain" (#3) deviate from IMMPACT standards, which define mild pain
as <4. Consider adjusting thresholds to align with these standards and justify the choice with
supporting evidence.
• The manuscript references, "Women with mild menstrual pain have been shown to display
almost no daily restrictions during menstruation," (Page 4, Participants). This statement is
disconnected. What is its relevance to the exclusion criteria for mild pain participants?
• Medical data were collected via telephone screening (Page 5, Recruitment Process). What steps
were taken to mitigate misclassification risks, especially for distinguishing between primary
and secondary dysmenorrhea? Did you confirm secondary dysmenorrhea diagnoses via clinical
records or additional diagnostic tools?
• Recruitment was conducted primarily through university students (Page 5, Recruitment).
Acknowledge the potential for selection bias and poor generalizability to the broader population.
Suggest additional recruitment strategies, such as outreach to community health organizations,
to diversify the participant pool.
• On Page 6, "Participants were instructed to collect two cortisol saliva samples," but the quality
and timing of sample collection cannot be ensured. Specify how you assessed adherence to the
protocol, such as using timestamps or monitoring participant compliance.
• The approach of averaging diary data for missing entries (Page 6, Statistical Analysis) may
reduce variability and obscure trends. Consider multiple imputation or sensitivity analyses as
alternative methods. Justify how the selected approach impacts result robustness.
• The manuscript uses NRS scales to evaluate anticipatory emotions and stress. Provide a
reference or rationale for the validity of this approach in measuring constructs such as expected
pain-related disability or negative emotions.
• Statistical tests include Mann-Whitney U and t-tests, but no adjustment for multiple
comparisons was made (Page 6, Statistical Analysis). Discuss the risk of inflated Type I errors
and provide a rationale for not applying corrections or exploratory frameworks like False
Discovery Rate.
• What combinations of variables were compared, such as mean vs. maximum pain? Provide
details on all tested relationships and their statistical outcomes to avoid selective reporting
• Wherever possible, report confidence intervals to better convey uncertainty in your findings
• The choice of statistical tests, including Mann-Whitney U-tests and t-tests, does not account
for any covariates or confounders, which is a significant limitation in an observational study
highly vulnerable to confounding effects. Observational studies require strategies that account
for potential confounding, such as regression models or propensity score methods, to provide
more robust and reliable estimates. The authors should either justify their choice of statistical
tests or revise their approach to address this vulnerability.
Results
•
While the manuscript briefly mentions that average values were used to handle missing diary
entries, this method is statistically suboptimal and could introduce bias, especially with small
sample sizes. The authors should provide a detailed description of the missing data pattern
(e.g., percentage of missingness by group and variable) and justify their imputation approach
or consider using more robust methods, such as multiple imputation or mixed-effects modeling,
to account for missing data.
• The reported correlational analyses are extensive but lack clarity in terms of how subgroups
were chosen and analyzed. Were there significant interactions between other psychological
variables (e.g., depression or stress) and menstrual pain? For transparency, a table summarizing
subgroup analyses and interaction terms should be included, specifying which relationships were
exploratory and which were hypothesis-driven.
• The fluctuating CAR results over the last 10 days before menstruation suggest that the timing
of cortisol collection may not align with peak stress responses. Consideration of diurnal cortisol
patterns or additional sampling points could provide more robust insights into the HPA axis's
role in anticipatory stress.
• The reported correlations between psychological variables (e.g., anticipatory emotions) and
menstrual pain should consider potential confounders, such as baseline levels of depression,
stress, or prior menstrual pain experiences. Were these controlled for? If not, the validity of the
findings could be compromised by unaccounted variability.
Discussion
• The absence of significant CAR differences between groups could reflect methodological
or biological factors. Discuss whether the two-sample protocol was sufficient to detect group
differences and consider whether individual variability in cortisol reactivity might obscure
group-level patterns. Comparisons with studies using more comprehensive CAR protocols
would strengthen this discussion.
• Beyond the lack of hormonal profiling, consider the potential role of cyclical hormonal
variations that might interact with anticipatory stress and pain perception. Were participants'
menstrual phases confirmed through biomarkers, or was cycle phase determined solely by self-
report? This could introduce significant variability in the observed relationships.
• The constructs of anticipatory emotions, stress, and anxiety are closely related and may overlap
conceptually and statistically. Clarify how these constructs were distinguished in the study,
both theoretically and in measurement. For example, were multicollinearity or intercorrelations
between these constructs tested? This is crucial for interpreting their independent contributions
to pain.
• The manuscript briefly touches on the concept of a "vicious cycle" in dysmenorrhea, but this
idea could be expanded. How does the interplay between anticipatory mechanisms and menstrual
pain align with existing chronic pain models? Consider integrating concepts from predictive
coding or central sensitization theories to strengthen the theoretical framework.
• While the manuscript suggests interventions targeting expectations and emotions,
it does not address feasibility or specific approaches. Would brief interventions like
expectation management, cognitive-behavioral therapy, or mindfulness-based stress reduction
be appropriate for this population? Discuss whether these findings could inform tailored
intervention strategies.
• Recruitment through a student portal introduces significant selection bias, particularly
in terms of socioeconomic and educational homogeneity. Highlight how this limits
generalizability to broader populations. Additionally, the lack of exclusion of conditions like
secondary dysmenorrhea or premenstrual syndrome undermines the study's focus on primary
dysmenorrhea.
•
Suggest additional avenues for research based on the study's findings. For instance, could
longitudinal designs clarify the directionality of the relationships between anticipatory emotions
and pain?
Figures and Tables
• Revise figures to include confidence intervals as error bars (Figures 1-3). Clearly annotate
statistically significant differences.
• Expand figure legends with explicit descriptions of methods and findings. For example, "Figure
2: Anticipatory stress trajectories (mean ± SE) over 10 days pre-menses. Significant group
differences observed on days -2 and -1."
• Consolidate tables to emphasize effect sizes and confidence intervals (Table 2). Replace
"p<0.001" with "Mean difference: 4.8 (95% CI: 3.9–5.7)."