Perioperative Vaginal Estrogen as Adjunct to Native Tissue Vaginal Apical Prolapse Repair: A Randomized Clinical Trial
Open accessAbstract
Importance: Surgical repairs of apical/uterovaginal prolapse are commonly performed using native tissue pelvic ligaments as the point of attachment for the vaginal cuff after a hysterectomy. Clinicians may recommend vaginal estrogen in an effort to reduce prolapse recurrence, but the effects of intravaginal estrogen on surgical prolapse management are uncertain. Objective: To compare the efficacy of perioperative vaginal estrogen vs placebo cream on prolapse recurrence following native tissue surgical prolapse repair. Design, Setting, and Participants: This randomized superiority clinical trial was conducted at 3 tertiary US clinical sites (Texas, Alabama, Rhode Island). Postmenopausal women (N = 206) with bothersome anterior and apical vaginal prolapse interested in surgical repair were enrolled in urogynecology clinics between December 2016 and February 2020. Interventions: The intervention was 1 g of conjugated estrogen cream (0.625 mg/g) or placebo, inserted vaginally nightly for 2 weeks and then twice weekly to complete at least 5 weeks of application preoperatively; this continued twice weekly for 12 months postoperatively. Participants underwent a vaginal hysterectomy (if uterus present) and standardized apical fixation (either uterosacral or sacrospinous ligament fixation). Main Outcomes and Measures: The primary outcome was time to failure of prolapse repair by 12 months after surgery defined by at least 1 of the following 3 outcomes: anatomical/objective prolapse of the anterior or posterior walls beyond the hymen or the apex descending more than one-third of the vaginal length, subjective vaginal bulge symptoms, or repeated prolapse treatment. Secondary outcomes included measures of urinary and sexual function, symptoms and signs of urogenital atrophy, and adverse events. Results: Of 206 postmenopausal women, 199 were randomized and 186 underwent surgery. The mean (SD) age of participants was 65 (6.7) years. The primary outcome was not significantly different for women receiving vaginal estrogen vs placebo through 12 months: 12-month failure incidence of 19% (n = 20) for vaginal estrogen vs 9% (n = 10) for placebo (adjusted hazard ratio, 1.97 [95% CI, 0.92-4.22]), with the anatomic recurrence component being most common, rather than vaginal bulge symptoms or prolapse repeated treatment. Masked surgeon assessment of vaginal tissue quality and estrogenization was significantly better in the vaginal estrogen group at the time of the operation. In the subset of participants with at least moderately bothersome vaginal atrophy symptoms at baseline (n = 109), the vaginal atrophy score for most bothersome symptom was significantly better at 12 months with vaginal estrogen. Conclusions and Relevance: Adjunctive perioperative vaginal estrogen application did not improve surgical success rates after native tissue transvaginal prolapse repair. Trial Registration: ClinicalTrials.gov Identifier: NCT02431897
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In Rahn 2023, a power calculation was not stated.
“Power calculation: not stated”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
The Methods section, under “Sample Size Calculation” (page not provided), explicitly states a power calculation. It specifies that 188 participants would provide 80% power at a two-sided α level of .05, contrary to the claim that no power calculation was stated. (LLM, conf=0.95)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn Rahn 2023, the risk of other bias was unclear.
“Other bias Unclear risk Industry‐sponsored trial”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
The Funding/Support section says the project was funded by the National Institute on Aging and two professional organizations; Pfizer provided the study drug through an investigator-initiated award. The Role of the Funder/Sponsor section says funders had no role in the study or publication decisions. The paper does not itself assign an ‘unclear’ other-bias rating, and its funding disclosure contradicts the stated reason of an industry-sponsored trial. (LLM, conf=0.82)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn Rahn 2023, the risk of selection bias from allocation concealment was low.
“Allocation concealment (selection bias) Low risk All surgeons, outcome assessors and participants masked to allocation concealment”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
The Randomization subsection of Methods says surgeons, outcome assessors, and participants were masked to intervention assignment, supporting the citing sentence’s description of masking. It does not describe how assignments were concealed before participants were enrolled, so the specific judgment of low selection-bias risk from allocation concealment is not established by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn Rahn 2023, the risk of selection bias from random sequence generation was low.
“Random sequence generation (selection bias) Low risk Computer generated 1:1 ratio”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
The Methods (Randomization; page not available) state that participants were randomized 1:1 to estrogen or placebo. Our copy does not specify that the sequence was computer-generated, so it does not establish the stated low-risk judgment for random sequence generation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn Rahn 2023, the risk of reporting bias from selective reporting was low.
“Selective reporting (reporting bias) Low risk No reporting bias detected. Trial pre‐registered”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
The Trial Registration entry lists ClinicalTrials.gov identifier NCT02431897, and Methods (Study Design) says the protocol and statistical analysis plan are available. The paper does not itself assess selective-reporting bias or establish that none was detected; Methods (Outcomes) also notes a post hoc redefinition of an outcome component. (LLM, conf=0.84)
Experimental — accuracy not yet measured
In Rahn 2023, the risk of attrition bias from incomplete outcome data was low.
“Incomplete outcome data (attrition bias) All outcomes Low risk Attrition rate < 10% in both arms”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
The Results (page unavailable) state that all 93 surgical participants in each arm returned for at least one postoperative assessment, and the 12-month physical-examination counts were 90 and 87. But the reported 12-month primary-outcome counts were 87 in the estrogen arm and 83 in the placebo arm; the latter is 10 fewer than 93, so the paper does not support the claim of less than 10% incomplete data in both arms for all outcomes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPerioperative vaginal estrogen cream did not improve recurrence rates compared with placebo; adjusted HR 1.97 (95% CI 0.92-4.22; P=0.08).
“The application of estrogen cream did not improve recurrence rates; the adjusted hazard ratio of failure for vaginal estrogen compared with placebo was 1.97 (95% CI, 0.92-4.22;P = 0.08).”
From Characteristics Associated With Surgical Failure After Native Tissue Apical Prolapse Repair (2024) · cites this paper as [8]
This study was a planned ancillary analysis of a randomized superiority trial (NCT02431897).
“This was a planned ancillary analysis of a randomized superiority trial (NCT02431897), the design of which and primary outcome report have been previously published.7,8”
From Characteristics Associated With Surgical Failure After Native Tissue Apical Prolapse Repair (2024) · cites this paper as [8]
Three trials with a total of 409 women evaluated POP surgery with or without vaginal oestrogen.
“POP surgery with or without vaginal oestrogen: three trials with a total of 409 women (Marschalek 2021; Nowakowski 2023; Rahn 2023).”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
There may be no evidence of a difference in bladder injury during POP surgery with or without vaginal oestrogen.
“Based on data from a single trial (Rahn 2023), there may be no evidence of a difference in bladder injury during POP surgery with or without vaginal oestrogen (OR 0.48, 95% CI 0.12 to 1.99; 1 study, 186 women; low‐certainty evidence; Analysis 12.1).”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
There may be no evidence of a difference in PGI-I scores for women undergoing POP surgery with or without vaginal oestrogen.
“Based on data from a single trial (Rahn 2023), there may be no evidence of a difference in PGI‐I scores for women undergoing POP surgery with or without vaginal oestrogen (OR 1.89, 95% CI 0.61 to 5.86; 1 study, 186 women; low‐certainty evidence; Analysis 12.4).”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
In Rahn 2023, the risk of performance bias from blinding of participants and personnel was low.
“Blinding of participants and personnel (performance bias) All outcomes Low risk Participants were blinded”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
In Rahn 2023, the risk of detection bias from blinding of outcome assessment was low.
“Blinding of outcome assessment (detection bias) All outcomes Low risk Surgeons and outcome assessors were blinded”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
In Rahn 2023, the randomisation method was not stated.
“Randomisation method: not stated”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
In Rahn 2023, the trial was registered (ClinicalTrials.gov Identifier: NCT02431897).
“Trial registration: ClinicalTrials.gov Identifier: NCT02431897”
From Perioperative interventions in pelvic organ prolapse surgery (2025) · cites this paper as Rahn 2023
The Methods (Study Design; page not available) identify this as a randomized trial but do not give a registration number. Searches of our copy for “NCT02431897” and “Trial Registration ClinicalTrials.gov” found no passage confirming that identifier. (LLM, conf=0.72)
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References 33 · Cited by 28
- Authors
- Rahn, D. D., Richter, H. E., Sung, V. W., Pruszynski, J. E., & Hynan, L. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Alabama at Birmingham (US)
- Women & Infants Hospital of Rhode Island (US)
- Corresponding author
- Rahn, David D.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2023-08-15
- Volume
- 330
- Issue
- 7
- Pages
- 615
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC10427941
- OpenAlex
- W4385827865
- Cited by
- 28
- References
- 33
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 6 · 2023: 2
- FWCI
- 5.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR003163)
- National Institute on Aging (R01AG047290)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (UG1HD054241)
- Topics
- Health Sciences › Medicine › Rheumatology › Pelvic floor disorders treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Health Sciences › Medicine › Obstetrics and Gynecology › Uterine Myomas and Treatments
- Keywords
- vaginal cream, uterovaginal prolapse, apical vaginal prolapse, sacrospinous ligament fixation, vaginal hysterectomy, postmenopausal women, prolapse recurrence, conjugated estrogens, vaginal atrophy, sexual function, urinary function
- MeSH terms
- Administration, Intravaginal, Aged, Estrogens, Conjugated (USP), Female, Humans, Hysterectomy, Hysterectomy, Vaginal, Middle Aged, Gynecologic Surgical Procedures, Uterine Prolapse, Vagina, Vaginal Creams, Foams, and Jellies, Treatment Outcome, Secondary Prevention, Pelvic Organ Prolapse
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