Preoperative Hormonal Priming
Perioperative vaginal estrogen can improve vaginal estrogenization and treat coexisting GSM, but IMPROVE did not demonstrate improved native-tissue apical prolapse repair success at 12 months or 3 years. The newer EVA trial reported better patient-reported recovery at 12 months, without better anatomical or composite surgical success.[16] Evidence for fewer postoperative UTIs is less certain and does not establish routine priming for every vaginal operation. Pessary studies address a separate, nonsurgical setting.[1][2][3][10]
For broader context, see Vaginal and topical estrogen, Vaginal DHEA, Ospemifene, and the clinical GSM article.
Biological rationale
Vaginal tissue is estrogen-responsive; postmenopausal hypoestrogenism thins epithelium, reduces collagen, increases MMP activity, and impairs wound healing — all of which could theoretically compromise the substrate of a surgical repair.[4][5]
Histologic evidence — Rahn 2014 biopsy RCT
Rahn 2014 randomized 30 postmenopausal women with ≥stage 2 POP to 6 weeks of preoperative conjugated estrogen cream (Premarin 0.625 mg/g, 1 g) vs placebo. Full-thickness vaginal-wall biopsies at hysterectomy:[4]
- Epithelial thickness ↑ 1.8× (p = 0.002)
- Muscularis thickness ↑ 2.7× (p = 0.088)
- Collagen type Iα1 mRNA ↑ 6.0× in the muscularis (p <0.05)
- Changes in a pro-anabolic matrix-protein profile
Animal model — Balgobin 2013
Ovariectomized guinea pigs treated with estradiol showed increased smooth muscle, vaginal-wall thickness, total / cross-linked collagen, and sustained 12-fold elevation of lysyl oxidase mRNA at 21 days post-injury vs near-baseline in estrogen-deprived animals — suggesting estrogen creates a matrix environment that optimizes long-term wound healing.[6]
Wound-healing meta-analysis — Vodegel 2022 (14 studies)
The review combined human and animal evidence; several strength, collagen, and vascular endpoints came from animal models. These surrogate results cannot establish better human prolapse-repair durability:[5]
| Parameter | SMD (95% CI) | Direction |
|---|---|---|
| Macroscopic wound closure | 1.82 (1.22–2.42) | ↑ |
| Tissue strength | 1.26 (0.53–1.99) | ↑ |
| Neovascularization | 1.13 (0.67–1.60) | ↑ |
| Collagen synthesis | 1.08 (0.42–1.74) | ↑ |
| Microscopic wound closure | 0.98 (0.66–1.29) | ↑ |
| Granulation tissue | 1.67 (0.54–2.79) | ↑ |
| Inflammatory response | −0.58 (−1.14 to −0.02) | ↓ |
| TGF-β1 levels | −1.68 (−2.52 to −0.83) | ↓ |
The mechanistic case is strong. The clinical translation is the story of the IMPROVE trial.
IMPROVE — multicenter randomized trial
The IMPROVE trial (Investigation to Minimize Prolapse Recurrence Of the Vagina using Estrogen) is a multicenter trial with longer-term follow-up — published in JAMA 2023 with 3-year follow-up in AJOG 2024.[1][3]
Design
- 3 tertiary US sites (Texas, Alabama, Rhode Island); randomized, double-blind, placebo-controlled superiority trial
- 206 enrolled; 199 randomized; 186 underwent surgery — postmenopausal women with bothersome anterior / apical POP (≥ stage 2)
- Intervention: 1 g conjugated estrogen cream (0.625 mg/g) or placebo, nightly × 2 weeks → twice weekly for ≥5 weeks preop, continued twice weekly for 12 months postop
- All participants: vaginal hysterectomy (if uterus present) + standardized uterosacral or sacrospinous ligament suspension
- Primary outcome: composite failure at 12 months (anterior/posterior prolapse beyond the hymen or apical descent greater than one-third vaginal length; subjective bulge symptoms; or retreatment)
12-month results[1]
| Outcome | Vaginal estrogen | Placebo | HR (95% CI) |
|---|---|---|---|
| Composite failure at 12 mo | 19% model estimate (20 events) | 9% model estimate (10 events) | 1.97 (0.92–4.22) — not significant |
| Anatomic recurrence (dominant failure mode) | Higher | Lower | — |
| Subjective bulge / retreatment | Rare | Rare | — |
| Surgeon-assessed tissue quality at surgery | Significantly better | — | p <0.05 |
| Atrophy symptoms at 12 mo (baseline-symptomatic subset, n = 109) | Significantly better | — | p <0.05 |
Trial authors' conclusion: "Adjunctive perioperative vaginal estrogen application did not improve surgical success rates after native-tissue transvaginal prolapse repair."[1]
3-year follow-up — Rahn 2024[3]
- Composite failure at 36 mo: 32.6% (estrogen) vs 26.8% (placebo); adjusted HR 1.55 (95% CI 0.90–2.66; p = 0.11)
- Per-protocol analysis: similar
- 94–95% of participants in both groups reported being "much or very much better" at 36 months — including 51 of 55 "surgical failures" — underscoring that most recurrences were asymptomatic anatomic descent without retreatment
- POP-Q, PGI-S, PFDI-20, and PFIQ-7 all improved significantly in both arms without between-group differences
- Substantial crossover at 36 months — 49% of the original estrogen group and 60% of the original placebo group were using vaginal estrogen (p = 0.15)
Bottom line: estrogen improved tissue appearance at surgery but did not translate into better surgical outcomes at 12 or 36 months.[1][3]
EVA — August 2026 multicenter trial
The EVA trial randomized 311 women across 22 Dutch hospitals to perioperative estriol cream or placebo before primary native-tissue repair for stage ≥2 POP; 293 underwent surgery and started the intervention. The regimen began 4–6 weeks before surgery and continued to 12 months afterward, with a two-week postoperative pause.[16]
At 12 months, 236 participants remained in follow-up, but the primary PGI-I response was available for 210: 97/106 (91.5%) versus 83/104 (79.8%) reported being much or very much improved (OR 2.73, 95% CI 1.18–6.28; p = 0.02). This roughly 12-percentage-point difference was smaller than the trial's prespecified 15-point threshold for clinical importance. Anatomical outcomes, composite surgical success and reintervention did not show a significant difference.[16]
The finding supports discussing symptom-focused adjunctive use. Substantial missing outcome data, only 12 months of follow-up and differences from IMPROVE in procedures and formulation limit interpretation. It does not establish a more durable repair or a benefit for every vaginal operation.[16]
Preoperative effect on pelvic-floor symptoms — IMPROVE ancillary
Rahn 2023 ancillary analysis of 7 weeks of preoperative vaginal estrogen on pelvic-floor symptoms before surgery (n = 191):[7]
| Symptom | Estrogen improved | Placebo improved | p |
|---|---|---|---|
| SUI (bothersome at baseline) | 50% | 43% | 0.78 |
| UUI | 43% | 31% | 0.41 |
| Urinary frequency | 41% | 26% | 0.18 |
| Dyspareunia | 42% | 48% | 0.49 |
| Most bothersome atrophy symptom (adherent) | Slightly more | — | 0.19 |
| Objective atrophy signs (adherent) | +1.54 | +0.69 | 0.01 |
Despite measurable objective improvement in vaginal estrogenization among adherent participants, the clinical-symptom improvement was inconclusive — urinary function, sexual function, dyspareunia, and atrophy symptoms did not reach statistical significance vs placebo.[7]
Other perioperative evidence
Marschalek 2021 (103 participants) reported fewer postoperative complications and less antibiotic use, although the masked surgical tissue assessment did not show a clear treatment difference. These secondary outcomes from one small trial need cautious interpretation.[9]
The 2018 Haya Cochrane review predates IMPROVE and other 2021–2023 trials; it cannot be their source. The later Sicilia 2025 systematic review summarizes ten RCTs and concludes that possible tissue and infection benefits remain limited by the evidence.[8][2]
Postoperative UTI reduction — a possible benefit
Taithongchai 2023 Cochrane review reported fewer postoperative UTIs with topical estrogen added to surgery, but stressed variation between contributing studies and insufficient evidence for firm overall conclusions.[10]
Sicilia 2025 BJOG systematic review (10 RCTs, n = 709) reported possible benefits but emphasized limited evidence: vaginal estrogen appeared to reduce postoperative UTIs and antibiotic use, while showing no significant impact on surgical failure or POP recurrence.[2]
The Cochrane authors cautioned that contributing studies varied substantially. IMPROVE itself found no statistically significant reduction in participants with UTI (19% vs 25%; p = 0.38). Routine preoperative estrogen solely as infection prophylaxis is therefore not established.[1][10]
Separate evidence in women with recurrent UTI is more supportive: the Chen 2021 meta-analysis showing vaginal estrogen reduces rUTI generally (RR 0.42) — see Vaginal and topical estrogen and Non-antibiotic UTI prevention.[11]
Pessary users — Zhou 2025 BMJ RCT
Zhou 2025 (420 randomized, 411 included in the modified intention-to-treat analysis; 12 academic centers in China) — postmenopausal women with ≥ stage 2 POP successfully fitted with ring pessaries, randomized to vaginal estrogen cream vs placebo for 12 months:[12]
- Pessary continuation with satisfaction: 87.0% (estrogen) vs 86.7% (placebo); risk difference 0.3% (95% CI −6.2 to 6.9; p = 0.92) — no difference
- Pessary-related adverse events reduced:
- Excessive discharge: 16.3% vs 25.6% (risk difference −9.3 percentage points; 95% CI −17.1 to −1.4)
- Vaginal erosion / bleeding: significantly less frequent
These secondary adverse-event findings may support individualized use in pessary users, but do not demonstrate improved pessary continuation or justify a perioperative surgical protocol.
Midurethral sling outcomes
Mesh exposure — Cadish 2016 retrospective cohort
n = 1,544 Kaiser Permanente cohort — preoperative vaginal estrogen was not associated with reduced mesh exposure after midurethral sling placement (OR 0.79; 95% CI 0.26–2.38; p = 0.67). Age, BMI, menopausal status, smoking, and diabetes were also not associated with exposure risk.[13]
QoL and sexual function — Caruso 2020 RCT
n = 96 postmenopausal women undergoing TOT — ultralow-dose vaginal estriol 0.03 mg daily × 16 weeks vs control:[14]
- Vaginal Maturation Index improved pre-op (43.1 vs 38.1; p = 0.04) and post-op (47.8 vs 38.1; p = 0.001)
- Greater FSFI improvement post-op (25.2 vs 17.2; p = 0.001)
- Greater mental-health QoL improvement pre-op (p = 0.02)
Reasonable interpretation: preoperative estrogen may not change sling-specific surgical outcomes but may improve overall perioperative QoL and sexual function.
Typical priming protocols
There is no validated universal priming protocol. The following are study regimens, not interchangeable labeled schedules for every product or vaginal operation:[1][4][7][8][10]
| Protocol | Formulation | Loading | Maintenance | Total | Context |
|---|---|---|---|---|---|
| IMPROVE | CEE cream 0.625 mg/g, 1 g | Nightly × 2 wk | 2×/wk | ≥5 wk preop + 12 mo postop | POP repair (USLS / SSLS) |
| Rahn 2014 biopsy RCT | CEE cream 0.625 mg/g, 1 g | Nightly × 2 wk | 2×/wk | 6 wk preop (range 4–8) | POP + hysterectomy |
| Marschalek 2021 | Estradiol cream 0.10 mg in 1 g | Daily | — | 6 wk preop | POP repair |
Guideline positions
ACOG's POP bulletin describes limited evidence for treating or preventing prolapse with estrogen. The 2023 Cochrane review searched through June 2022 and therefore predates IMPROVE's published surgical results; its uncertainty should be interpreted alongside the later trial and follow-up. Prescribe for an individual GSM or recurrent-UTI indication when appropriate, rather than promising prevention of repair failure.[15][10][1][3]
What the evidence supports — and what it does not
| Claimed benefit | Evidence | Verdict |
|---|---|---|
| Improves tissue quality (histology, collagen, VMI) | Small human biopsy RCT plus mixed human/animal meta-analysis | Supported[4][5] |
| Improves surgeon-perceived tissue quality | Trial findings differ (IMPROVE, Marschalek) | Improvement in IMPROVE; no clear masked tissue-quality difference in Marschalek[1][9] |
| Reduces postoperative UTIs | Heterogeneous small studies; limited certainty | Possible benefit[10] |
| Reduces postoperative complications / antibiotic use | Limited (1 RCT) | Possibly supported[9] |
| Reduces pessary-related erosion / bleeding | Secondary outcomes in multicenter RCT | Possible benefit; continuation unchanged[12] |
| Reduces prolapse recurrence | Strong negative evidence (IMPROVE 12-mo + 3-y) | NOT supported[1][3] |
| Improves surgical success rates | Strong negative evidence | NOT supported[1][3] |
| Improves preoperative urinary symptoms | Inconclusive (IMPROVE ancillary) | NOT supported[7] |
| Improves preoperative sexual function | Inconclusive | NOT supported[7] |
| Reduces mesh exposure after sling | Negative (retrospective n = 1,544) | NOT supported[13] |
Evidence Summary
| Application | Evidence level | Key source |
|---|---|---|
| Tissue quality improvement (histology, mRNA) | Level 1 (biopsy RCT + meta) | Rahn 2014[4]; Vodegel 2022[5] |
| Prolapse-recurrence prevention (12 mo) | Level 1 (large RCT) | IMPROVE — Rahn 2023[1] |
| Patient-reported recovery after primary repair | Multicenter RCT; 311 randomized, 210 primary-outcome responses | EVA 2026[16] |
| Prolapse-recurrence prevention (36 mo) | Level 1 | IMPROVE 3-year — Rahn 2024[3] |
| Preoperative pelvic-floor symptoms | Level 1 (ancillary) | Rahn 2023[7] |
| Postoperative UTI reduction | Systematic review; heterogeneous small studies | Taithongchai 2023[10]; Sicilia 2025[2] |
| Postoperative complications / antibiotic use | Level 1 (RCT) | Marschalek 2021[9] |
| Pessary continuation and complications | Level 1 (multicenter RCT) | Zhou 2025 BMJ[12] |
| Sling mesh exposure | Level 3 (retrospective) | Cadish 2016[13] |
| Preoperative QoL / sexual function (sling) | Level 2 (RCT) | Caruso 2020[14] |
Clinical Positioning
- Treat coexisting GSM or recurrent UTI when indicated. Routine priming has not been shown to prevent prolapse recurrence; improvement in tissue appearance is a surrogate outcome.[1][3]
- Counsel that improved repair success was not demonstrated, rather than promising no recurrence or claiming estrogen causes failure. The trial was not designed to prove equivalence.[1][3]
- Use formulation-specific dosing. IMPROVE's regimen is a trial protocol. A 10 µg estradiol tablet generally uses a two-week daily loading period followed by twice-weekly maintenance; see the prescribing hub.
- Pessary findings apply to pessary care. Zhou's trial found fewer selected adverse events, with no continuation advantage.[12]
- DHEA is not an automatic safe alternative when estrogen is contraindicated. It is metabolized to estrogens and androgens, and its label warns about breast-cancer history. No established priming benefit justifies routine substitution; see prasterone.
- Continue GSM treatment according to benefit, tolerability, patient preference, and the current product label; product-specific FDA revisions do not remove every contraindication or follow-up need.
See Also
- Vaginal and topical estrogen
- Vaginal DHEA
- Ospemifene
- Perioperative antibiotic prophylaxis
- GSM (clinical)
References
1. Rahn DD, Richter HE, Sung VW, Pruszynski JE, Hynan LS. "Perioperative vaginal estrogen as adjunct to native-tissue vaginal apical prolapse repair: a randomized clinical trial (IMPROVE)." JAMA. 2023;330(7):615–625. doi:10.1001/jama.2023.12317
2. Sicilia G, Vitale SG, D'Alterio MN, et al. "The role of vaginal oestrogen therapy in postmenopausal women with pelvic organ prolapse: does it have any impact on perioperative outcomes? A systematic review of randomised controlled trials." BJOG. 2025. doi:10.1111/1471-0528.18260
3. Rahn DD, Richter HE, Sung VW, Pruszynski JE. "Three-year outcomes of a randomized clinical trial of perioperative vaginal estrogen as adjunct to native-tissue vaginal apical prolapse repair." Am J Obstet Gynecol. 2024;231(2):263.e1–263.e10. doi:10.1016/j.ajog.2024.04.042
4. Rahn DD, Good MM, Roshanravan SM, et al. "Effects of preoperative local estrogen in postmenopausal women with prolapse: a randomized trial." J Clin Endocrinol Metab. 2014;99(10):3728–3736. doi:10.1210/jc.2014-1216
5. Vodegel EV, Kastelein AW, Jansen CHJR, et al. "The effects of oestrogen on vaginal wound healing: a systematic review and meta-analysis." Neurourol Urodyn. 2022;41(1):115–126. doi:10.1002/nau.24819
6. Balgobin S, Montoya TI, Shi H, et al. "Estrogen alters remodeling of the vaginal wall after surgical injury in guinea pigs." Biol Reprod. 2013;89(6):138. doi:10.1095/biolreprod.113.112367
7. Rahn DD, Richter HE, Sung VW, Hynan LS, Pruszynski JE. "Effects of preoperative intravaginal estrogen on pelvic floor disorder symptoms in postmenopausal women with pelvic organ prolapse." Am J Obstet Gynecol. 2023;229(3):309.e1–309.e10. doi:10.1016/j.ajog.2023.05.023
8. Haya N, Feiner B, Baessler K, Christmann-Schmid C, Maher C. "Perioperative interventions in pelvic organ prolapse surgery." Cochrane Database Syst Rev. 2018;8:CD013105. doi:10.1002/14651858.CD013105
9. Marschalek ML, Bodner K, Kimberger O, et al. "Surgical assessment of tissue quality during pelvic organ prolapse repair in postmenopausal women pre-treated either with locally applied estrogen or placebo: results of a double-masked, placebo-controlled, multicenter trial." J Clin Med. 2021;10(11):2531. doi:10.3390/jcm10112531
10. Taithongchai A, Johnson EE, Ismail SI, et al. "Oestrogen therapy for treating pelvic organ prolapse in postmenopausal women." Cochrane Database Syst Rev. 2023;7:CD014592. doi:10.1002/14651858.CD014592.pub2
11. Chen YY, Su TH, Lau HH. "Estrogen for the prevention of recurrent urinary tract infections in postmenopausal women: a meta-analysis of randomized controlled trials." Int Urogynecol J. 2021;32(1):17–25. doi:10.1007/s00192-020-04397-z
12. Zhou Y, Yin R, Zhang Y, et al. "Effects of intravaginal conjugated oestrogen on pessary continuation for pelvic organ prolapse: multicentre, randomised, double-blind, placebo-controlled trial." BMJ. 2025;389:e084418. doi:10.1136/bmj-2025-084418
13. Cadish LA, West EH, Sisto J, et al. "Preoperative vaginal estrogen and midurethral sling exposure: a retrospective cohort study." Int Urogynecol J. 2016;27(3):413–417. doi:10.1007/s00192-015-2810-x
14. Caruso S, Cianci A, Sarpietro G, et al. "Ultralow 0.03 mg vaginal estriol in postmenopausal women who underwent surgical treatment for stress urinary incontinence: effects on quality of life and sexual function." Menopause. 2020;27(2):162–169. doi:10.1097/GME.0000000000001446
15. American College of Obstetricians and Gynecologists. "Pelvic organ prolapse: ACOG Practice Bulletin No. 214." Obstet Gynecol. 2019;134(5):e126–e142. doi:10.1097/AOG.0000000000003519
16. Vodegel EV, van Rest K, Speksnijder L, et al; EVA Study Group. "Vaginal Oestrogen Therapy for Postmenopausal Women Undergoing Prolapse Surgery: A Multicentre Double-Blind Randomised Placebo-Controlled Clinical Trial." BJOG. Published online August 28, 2026. doi:10.1111/1471-0528.70311. Full article.