Preoperative Hormonal Priming
Preoperative vaginal estrogen priming — typically 4–6 weeks before vaginal surgery — is a widely practiced but not evidence-based intervention in contemporary urogynecology. It reliably improves surrogate markers of tissue quality (epithelial thickness, collagen content, surgeon-perceived tissue robustness), but the landmark IMPROVE trial and subsequent systematic reviews have now shown that it does not reduce prolapse recurrence, improve surgical success, or improve pelvic-floor symptoms at 12 months or 3 years.[1][2][3] Two benefits are reproducibly supported in RCT evidence: reduced postoperative UTIs and antibiotic use, and reduced pessary-related complications. Those are the defensible reasons to use it in 2026.
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)
Estrogen improved virtually every wound-healing parameter measured:[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 — the definitive RCT
The IMPROVE trial (Investigation to Minimize Prolapse Recurrence Of the Vagina using Estrogen) is the largest and most rigorous RCT on this question — 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
- n = 206 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 (anatomic recurrence beyond hymen OR subjective bulge symptoms OR retreatment)
12-month results[1]
| Outcome | Vaginal estrogen | Placebo | HR (95% CI) |
|---|---|---|---|
| Composite failure at 12 mo | 19% (20/104) | 9% (10/102) | 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]
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 RCTs of perioperative vaginal estrogen — Cochrane 2024
The Cochrane review of perioperative interventions in POP surgery identified three RCTs (total n = 409):[8]
| Study | n | Regimen | Duration | Key finding |
|---|---|---|---|---|
| Marschalek 2021 | 103 | Estradiol cream 0.10 mg in 1 g vs placebo | 6 wk preop | Surgeons rated tissue similarly, though rating correlated with treatment; postoperative complications (p = 0.045) and antibiotic use (p = 0.003) significantly lower with estrogen[9] |
| Nowakowski 2023 | 100 | Estradiol 10 µg vs DHEA 6.5 mg vs chlorquinaldolum/metronidazole | 42 d preop | Compared 3 priming strategies — one of the few trials to address non-estrogen alternatives |
| Rahn 2023 — IMPROVE | 206 | CEE cream 0.625 mg/g, 1 g vs placebo | ≥5 wk preop + 12 mo postop | No improvement in surgical success; improved tissue appearance and atrophy signs[1] |
Marschalek's complication / antibiotic-use signal is the clearest clinical benefit demonstrated in an RCT.
Postoperative UTI reduction — the clearest benefit
Taithongchai 2023 Cochrane review pooled 5 studies (n = 483): topical estrogen + surgery produced fewer postoperative UTIs than surgery alone — RR 0.49 (95% CI 0.26–0.90).[10]
Sicilia 2025 BJOG systematic review (10 RCTs, n = 709) confirmed: vaginal estrogen appeared to reduce postoperative UTIs and antibiotic use, while showing no significant impact on surgical failure or POP recurrence.[2]
This is consistent with the broader 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 (n = 420, 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% (p < 0.01)
- Vaginal erosion / bleeding: significantly less frequent
The pessary-tolerance signal is a meaningful clinical benefit that sits alongside UTI reduction as the most defensible reason to use vaginal estrogen perioperatively.
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
No standardized protocol; the regimens used in RCTs and practice:[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 |
| Nowakowski 2023 | Estradiol 10 µg tablet | Daily | — | 42 d preop | POP repair |
| Verghese Cochrane | CEE cream 0.5–1.0 g | Nightly | — | 2–12 wk preop | Post-hysterectomy POP repair |
| Common clinical practice | Any low-dose vaginal estrogen | Nightly × 2 wk | 2×/wk | 4–6 wk preop | Any vaginal surgery |
Guideline positions
No major society has issued a strong recommendation for or against:
- ACOG Practice Bulletin 214 (POP, 2019): "There is limited evidence for the treatment or prevention of POP with local or systemic estrogen. However, some clinicians believe that local estrogen may help with the vaginal irritation associated with POP."[15]
- Cochrane 2023: "Many of the outcome measures in the included studies, such as vaginal epithelial thickness, are surrogate outcomes for tissue quality… No studies have investigated whether estrogen can improve the long-term integrity of surgical repair."[10]
- IMPROVE authors (JAMA 2023): "Some experts recommend 4 or more weeks of preoperative local estrogen before reconstructive surgery in postmenopausal patients without adequate tissue estrogen, but this is not evidence based."[1]
What the evidence supports — and what it does not
| Claimed benefit | Evidence | Verdict |
|---|---|---|
| Improves tissue quality (histology, collagen, VMI) | Strong (RCT biopsy + meta-analysis) | Supported[4][5] |
| Improves surgeon-perceived tissue quality | Moderate (IMPROVE, Marschalek) | Supported[1][9] |
| Reduces postoperative UTIs | Moderate (Cochrane RR 0.49) | Supported[10] |
| Reduces postoperative complications / antibiotic use | Limited (1 RCT) | Possibly supported[9] |
| Reduces pessary-related erosion / bleeding | Strong (BMJ 2025 RCT) | Supported[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] |
| 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 | Level 1 (Cochrane meta) | 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
- Prescribe preoperative vaginal estrogen for the benefits that RCT evidence supports — postoperative UTI reduction, pessary tolerance, GSM symptom management — not for prolapse-recurrence prevention. The IMPROVE 12-month and 3-year data are definitive on that point.[1][3][10]
- The 7.7% placebo-adjusted tissue benefit does not translate to improved surgical outcomes. Surgeons reliably rate the tissue as better, but recurrence rates trended numerically higher in the estrogen arm at 12 months and 3 years.[1][3]
- Standard regimen for GSM-dominant symptoms: CEE cream 0.625 mg/g 1 g nightly × 2 weeks, then 2×/week for 4–6 weeks preop and continued postop (IMPROVE protocol).[1]
- Standard alternatives include 10 µg estradiol tablet daily or the 7.5 µg/day estradiol ring — see Vaginal and topical estrogen.
- Counsel patients explicitly that preoperative estrogen will not reduce their risk of prolapse recurrence based on IMPROVE — this protects against unrealistic expectations.[1][3]
- The pessary-tolerance data from Zhou 2025 are the strongest 2025-era reason to prescribe vaginal estrogen to pessary users — erosion and bleeding are meaningfully reduced even if continuation rates are unchanged.[12]
- The Marschalek postoperative-complication signal (p = 0.045) and antibiotic-use signal (p = 0.003) are single-RCT data but directionally aligned with the UTI literature — reasonable secondary support for perioperative use.[9]
- Sling mesh exposure does not fall with preoperative estrogen; do not base sling prep on this rationale.[13]
- For estrogen-contraindicated patients, vaginal DHEA (prasterone 6.5 mg) has been studied as a preoperative priming agent in Nowakowski 2023 and is the most defensible non-estrogen alternative, though data are limited. See Vaginal DHEA.[8]
- Post-hormone-boxed-warning-removal (November 2025) there is no regulatory pressure to limit duration — continue postoperatively for GSM symptom control and UTI prevention as clinically indicated.
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