Effects of intravaginal conjugated oestrogen on pessary continuation for pelvic organ prolapse: multicentre, randomised, double blind, placebo controlled trial.
Zhou Y, Yin R, Zhang Y, Wang X, Jin F, Li X, Peng C, Wang P, Shen H, Weng Q, Xie H, Wang H, Jiang B, Zhou K, Liang N, He Y, Dai Y, Fang Z, Liang S, Zhang Y, Morse A, Zhu L
- DOI
- 10.1136/bmj-2025-084418
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-21
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/da7f6001-33aa-415d-90bb-bd27b38b5f10 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 9 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted, rigorously reported randomised controlled trial. The study design, ethical approvals, and statistical reporting are strong, with clear data and code availability. Minor reporting gaps include lack of explicit statistical software name, CONSORT adherence statement, and regulatory compliance statement, plus minor copyedit issues.
Both reviewers classified the study as interventional, and I adopted that. The evaluation covered all eight dimensions; not applicable sub-criteria (e.g., animal-related, cell lines) were excluded. The statistics verification checked only 3 tests (all consistent); other statistics were not machine-verified. The reproducibility check found 1 link but could not confirm it was live.
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
Recomputed 3 tests: 3 consistent, 0 inconsistent; 3 via agent-written checks.
- CONSISTENTreported p = .920 · recomputed p = .928Reviewers 1, 2Primary outcome risk difference p-value
“There was no statistically significant difference between the two groups (risk difference 0.3%, 95% confidence interval −6.2% to 6.9%, P=0.92).”
Taken as given: The risk difference is 0.3% (0.003).; The 95% confidence interval is -6.2% to 6.9% (-0.062 to 0.069).; The p-value is two-sided.Method: Recomputed p-value from the risk difference and its 95% confidence interval using the normal approximation.How we recomputed it: pCI(0.003, -0.062, 0.069, 0) - CONSISTENTreported p = .940 · recomputed p = .947Reviewer 2Pessary continuation rate difference p-value
“Pessary continuation | 186/208 (89.4) | 182/203 (89.7) | −0.2 (−6.1 to 5.7) | 0.94”
Taken as given: The risk difference is -0.2% (-0.002) with 95% CI -6.1% to 5.7%.; The CI is two-sided at 95%.; The p-value is two-tailed.Method: Recomputed p-value from the estimate and 95% CI using the normal approximation (pCI function).How we recomputed it: pCI(-0.002, -0.061, 0.057, 0) - CONSISTENTreported p = .730 · recomputed p = .737Reviewer 2Feeling satisfied p-value
“Feeling satisfied | 181/186 (97.3) | 176/182 (96.7) | 0.6 (−2.9 to 4.1) | 0.73”
Taken as given: The risk difference is 0.6% (0.006) with 95% CI -2.9% to 4.1%.; The CI is two-sided at 95%.; The p-value is two-tailed.Method: Recomputed p-value from the estimate and 95% CI using the normal approximation (pCI function).How we recomputed it: pCI(0.006, -0.029, 0.041, 0)
- lowinternal contradictionThe abstract reports 411 participants in the mITT analysis, but the flow diagram mentions 420 randomised and 411 included. The numbers are consistent, but the footnote in Table 2 mentions 181 and 184 completing questionnaires at six months, which may not reconcile with the mITT numbers.
“† 181 participants in oestrogen group and 184 participants in placebo group completed questionnaires at six months.”
Table 2Find in source - lowinternal contradictionThe number of participants completing questionnaires at six months differs between the text and the table footnote.
“† 181 participants in oestrogen group and 184 participants in placebo group completed questionnaires at six months.”
Table 2Find in source
Overstated conclusions
1 finding · worst lowConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Conclusions only partially backed by the presented evidenceAssessed
3 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2Vaginal oestrogen might be associated with a lower risk of common adverse events.The claim is supported for some adverse events (excessive discharge, erosion/ulcer, bleeding) but these are secondary outcomes and the authors appropriately caution interpretation.Evidence: Secondary outcomes show lower rates of excessive discharge, vaginal erosion/ulcer, and vaginal bleeding in the oestrogen group.
“Excessive discharge (34/208 (16.3%) v 52/203 (25.6%); −9.3%, −17.1% to −1.4%), vaginal erosion or ulcer (4/208 (1.9%) v 14/203 (6.9%); −5.0%, −8.9% to −1.0%), and vaginal bleeding (3/208 (1.4%) v 13/203 (6.4%); −5.0%, −8.7% to −1.2%) were less common in the vaginal oestrogen group.”
AbstractFind in source - supportedReviewers 1, 2Vaginal oestrogen did not improve pessary continuation with satisfaction.The primary outcome showed no significant difference, supporting the claim.Evidence: Primary outcome: 181/208 (87.0%) vs 176/203 (86.7%), risk difference 0.3%, 95% CI -6.2% to 6.9%, P=0.92.
“Pessary continuation rate with satisfaction did not differ significantly between the oestrogen group and the placebo group (181/208 (87.0%) v 176/203 (86.7%); risk difference 0.3%, 95% confidence interval −6.2% to 6.9%; P=0.92).”
AbstractFind in source - supportedReviewers 1, 2The clinical decision to use vaginal oestrogen should take into account its benefits and risks and the patient’s personal preferences.This is a reasonable conclusion based on the findings.Evidence: The study found no benefit for the primary outcome but potential benefits for some adverse events.
“The clinical decision to use vaginal oestrogen should take into account its benefits and risks and the patient’s personal preferences.”
ConclusionFind in source
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
None foundRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
Checked — nothing surfaced.
The introduction cites prior studies and a Cochrane review, noting limitations such as small sample sizes and lack of patient-reported outcomes. The rationale for the trial is clearly linked to these gaps, and the study aims to address them with a larger, blinded, placebo-controlled design.
“A Cochrane review published in 2023 identified three randomised controlled trials that assessed oestrogen treatment in conjunction with vaginal pessaries versus vaginal pessaries alone. None of these studies examined patient reported subjective improvement of POP symptoms, and they only reported reduction in minor adverse vaginal events including bacterial vaginosis and vaginal ulcers. Additionally, they were small studies (with 216 patients in total) and had methodological issues including blinding.”
“Therefore, there is a need for studies with sufficient power to assess the effects of oestrogen on pessary use over a longer time frame.”
“To address the evidence gap, we conducted a multicentre, randomised, double blind, placebo controlled trial to compare the efficacy of intravaginal oestrogen cream versus placebo cream in the pessary treatment outcomes for POP.”
“A Cochrane review published in 2023 identified three randomised controlled trials that assessed oestrogen treatment in conjunction with vaginal pessaries versus vaginal pessaries alone. None of these studies examined patient reported subjective improvement of POP symptoms, and they only reported reduction in minor adverse vaginal events including bacterial vaginosis and vaginal ulcers. Additionally, they were small studies (with 216 patients in total) and had methodological issues including blinding.”
“Therefore, there is a need for studies with sufficient power to assess the effects of oestrogen on pessary use over a longer time frame.”
“To address the evidence gap, we conducted a multicentre, randomised, double blind, placebo controlled trial to compare the efficacy of intravaginal oestrogen cream versus placebo cream in the pessary treatment outcomes for POP.”
Randomization used a centrally managed block scheme with stratification by centre, and blinding was maintained for investigators, participants, care providers, and outcome assessors. A sample size calculation was performed, and inclusion/exclusion criteria were pre-specified. The modified intention-to-treat analysis is appropriate for a clinical trial.
“Participants who provided informed consent were enrolled through a web based electronic system and randomised (1:1) to receive vaginal conjugated oestrogen cream or placebo cream using a centrally managed, block randomisation scheme (block size of 4), stratified by centre.”
“Investigators, participants, care providers, and outcome assessors were blinded to group assignments.”
“The sample size was based on detecting a 14% absolute difference in continuation rates with 80% power and 5% significance, assuming 20% dropout, yielding a target of 420 participants.”
“Participants who provided informed consent were enrolled through a web based electronic system and randomised (1:1) to receive vaginal conjugated oestrogen cream or placebo cream using a centrally managed, block randomisation scheme (block size of 4), stratified by centre.”
“Investigators, participants, care providers, and outcome assessors were blinded to group assignments. The two products were identical in packaging, colour, texture, and scent.”
“The sample size was based on detecting a 14% absolute difference in continuation rates with 80% power and 5% significance, assuming 20% dropout, yielding a target of 420 participants.”
Sex is reported (all postmenopausal women). Age, BMI, and health status are reported in baseline characteristics. Demographics include education, smoking, diabetes, hypertension, and other comorbidities. Species/strain and housing conditions are not applicable for a human trial.
“Postmenopausal women with symptomatic pelvic organ prolapse ≥stage 2”
“The mean age of participants was 66 years (standard deviation 7.6), the mean body mass index was 23.9 (standard deviation 2.6), and the median menopause duration was 16 years (interquartile range 10-22)”
The paper states that ethical approval was obtained from the institutional review board of Peking Union Medical College Hospital with a protocol number, and all participants provided written informed consent. This meets the requirements for human research.
“All participants provided written informed consent and ethical approval was obtained from the institutional review board of Peking Union Medical College Hospital (ZS-2164).”
“All participants provided written informed consent and ethical approval was obtained from the institutional review board of Peking Union Medical College Hospital (Beijing).”
“All participants provided written informed consent and ethical approval was obtained from the institutional review board of Peking Union Medical College Hospital (ZS-2164).”
“All participants provided written informed consent”
The trial uses a drug product, which is identified by name and dose. The manufacturer is mentioned. Statistical software is identified in the methods. No other biological resources are used.
“Participants applied 1 g of conjugated oestrogen (0.625 mg/g) or placebo cream vaginally every night for two weeks, then twice weekly for 12 months.”
“Conjugated oestrogen cream was provided by Xinjiang Nuziline Bio-Pharmaceutical Co.”
“Conjugated oestrogen cream was provided by Xinjiang Nuziline Bio-Pharmaceutical Co.”
The primary outcome is reported with risk differences and 95% confidence intervals. Secondary outcomes use mixed effects models. Exact p-values are reported for the primary outcome. The paper reports effect sizes with confidence intervals, which is adequate. Statistical software is identified.
“There was no statistically significant difference between the two groups (risk difference 0.3%, 95% confidence interval −6.2% to 6.9%, P=0.92).”
“Secondary outcomes were compared using mixed effects models.”
“There was no statistically significant difference between the two groups (risk difference 0.3%, 95% confidence interval −6.2% to 6.9%, P=0.92).”
“Secondary outcomes were compared using mixed effects models.”
The data availability statement provides a direct link to a public repository, and the code is available in supplemental files. This meets the criteria for adequate data sharing.
“The data underlying the findings in this paper are openly and publicly available and can be found here: https://www.ncmi.cn//phda/dataDetails.do?id=CSTR:17970.14.A0026.202505.23.V1.0 .”
“The code used to analyse the data in the paper can be found in the supplemental files.”
“The data underlying the findings in this paper are openly and publicly available and can be found here: https://www.ncmi.cn//phda/dataDetails.do?id=CSTR:17970.14.A0026.202505.23.V1.0”
“The code used to analyse the data in the paper can be found in the supplemental files.”
The trial is registered with ClinicalTrials.gov. Methods are comprehensive. Limitations are explicitly discussed. Conclusions are proportional to the evidence. Funding and competing interests are declared.
“Trial registration ClinicalTrials.gov NCT04393194 .”
“There are also some limitations. Firstly, we focused exclusively on patients who were fitted with ring pessaries with support because this is a common initial choice for pessary treatment, so the study does not necessarily represent the situation with other pessary types.”
“Funding: The trial was funded by the National Key R&D Program of China (2023YFC2706000; 2023YFC2706001), the National Key Clinical Specialty Construction Project (U114000), and National High-level Hospital Clinical Research Funding (No 2022-PUMCH-C-031).”
“Trial registration ClinicalTrials.gov NCT04393194”
“There are also some limitations. Firstly, we focused exclusively on patients who were fitted with ring pessaries with support because this is a common initial choice for pessary treatment, so the study does not necessarily represent the situation with other pessary types.”
“Funding: The trial was funded by the National Key R&D Program of China (2023YFC2706000; 2023YFC2706001), the National Key Clinical Specialty Construction Project (U114000), and National High-level Hospital Clinical Research Funding (No 2022-PUMCH-C-031).”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 22 references by DOI: 21 verified — 1 no DOI (shown, not verified).
- NO DOIEffect of local estrogen cream on vaginal health after pessary use for prolapsed pelvic organ: a randomized controlled trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link found; not probed for liveness in this run.
- datahttps://www.ncmi.cn//phda/dataDetails.do?id=CSTR:17970.14.A0026.202505.23.V1.0UNVERIFIEDHTTP 403Liveness indeterminate — content not checked.
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly consistency, typo, clarity.
- MINORtypoAbstract, Results“Pessary continuation rate with satisfaction did not differ significantly between the oestrogen group and the placebo group (181/208 (87.0%) v 176/203 (86.7%); risk difference 0.3%, 95% confidence interval −6.2% to 6.9%; P=0.92).”→ Consider using 'vs.' instead of 'v' for consistency.Minor style issue.
- MINORconsistencyTable 2, footnote“† 181 participants in oestrogen group and 184 participants in placebo group completed questionnaires at six months.”→ Ensure the numbers match the text in the results section.Potential inconsistency in the number of participants completing questionnaires.
- MINORconsistencyAbstract, Results“181/208 (87.0%) v 176/203 (86.7%)”→ Use 'vs' consistently instead of 'v'.The abbreviation 'v' is used for 'versus' in the abstract and results; consider standardizing to 'vs'.
- MINORclarityMethods, Outcomes“The composite primary outcome was defined as pessary continuation and a response of very much better or much better to the Patient Impression of Improvement (PGI-I) questionnaire at 12 months.”→ Clarify that 'Patient Impression of Improvement' should be 'Patient Global Impression of Improvement' (PGI-I) for consistency with the abstract.The abstract uses 'Patient Global Impression of Improvement' while the methods use 'Patient Impression of Improvement'.
- MINORotherTable 2, footnote“† 181 participants in oestrogen group and 184 participants in placebo group completed questionnaires at six months.”→ Verify the number of participants completing questionnaires at six months; the text mentions 181 and 184, but the table shows 208 and 203 randomized.The footnote numbers may be correct but should be cross-checked with the flow diagram.
The published work is robust and methodologically sound. An informed reader should weigh the minor reporting gaps (software name, CONSORT adherence, regulatory compliance) and the minor internal inconsistencies flagged in the copyedit and integrity checks. No erratum is warranted for the core findings, but the authors should consider issuing a correction for the minor inconsistencies and clarifying the reporting gaps.
- 1.HIGHreportingIn the Methods section, explicitly name the statistical software and version used for all analyses (e.g., R version 4.3.1, SAS 9.4).Both reviewers flagged that the software is not explicitly named, which is a reproducibility gap.
- 2.HIGHreportingAdd a statement of adherence to the CONSORT reporting guideline in the Methods or a dedicated section.Reviewer 2 noted that the reporting guideline is not explicitly mentioned, which is a transparency gap for a clinical trial.
- 3.HIGHethicsIn the Ethics statements, explicitly state compliance with the Declaration of Helsinki or ICH-GCP guidelines.Reviewer 2 flagged that regulatory compliance is not explicitly named, which is a minor ethics reporting gap.
- 4.MEDIUMcopyeditStandardize the abbreviation for 'versus' to 'vs.' throughout the abstract and results (currently 'v' is used).Copyedit flagged inconsistent use of 'v' vs 'vs'.
- 5.MEDIUMcopyeditClarify the terminology for the Patient Global Impression of Improvement (PGI-I) in the Methods; the abstract uses 'Patient Global Impression of Improvement' while the Methods use 'Patient Impression of Improvement'.Copyedit flagged inconsistent terminology that could confuse readers.
- 6.MEDIUMcopyeditCross-check and reconcile the number of participants completing questionnaires at six months (181 in oestrogen group, 184 in placebo group) between the text and Table 2 footnote.Copyedit and integrity checks flagged a potential inconsistency in these numbers.
- 7.MEDIUMdata codeVerify that the data repository link (https://www.ncmi.cn//phda/dataDetails.do?id=CSTR:17970.14.A0026.202505.23.V1.0) is live and accessible, and clarify any access requirements.The reproducibility check could not confirm the link was live; a broken link would undermine the data availability statement.
- 8.MEDIUMdata codeConsider depositing the analysis code in a public repository (e.g., GitHub) with a DOI, in addition to supplemental files.Reviewer 2 suggested this to enhance code sharing and long-term accessibility.
- 9.LOWreportingAdd a CONSORT flow diagram to the main text to improve transparency of participant flow.Reviewer 1 suggested this as an improvement for reporting transparency.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
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Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
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