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 found more women reporting 'much' or 'very much' improvement in prolapse symptoms on PGI-I at 12 months (97/106 versus 83/104); anatomical and composite surgical success did not differ significantly.[16] Evidence for fewer postoperative UTIs remains uncertain. 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) versus placebo. Full-thickness vaginal-wall biopsies at hysterectomy; the tissue changes below are for drug-adherent participants (8 estrogen, 13 placebo):[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
In ovariectomized guinea pigs given systemic estradiol (50 µg/kg/day), smooth muscle, vaginal-wall thickness, and total and cross-linked collagen increased; lysyl oxidase mRNA remained 12-fold elevated 21 days after injury versus near-baseline levels without estradiol.[6]
Wound-healing meta-analysis — Vodegel 2022 (14 studies; 11 in the meta-analysis)
The review combined human and animal evidence; several strength, collagen, and vascular endpoints came from animal models.[5]
| Parameter | SMD (95% CI) | Direction | Species |
|---|---|---|---|
| Macroscopic wound closure | 1.82 (1.22–2.42) | ↑ | Women and animals |
| Tissue strength | 1.26 (0.53–1.99) | ↑ | Animals |
| Neovascularization | 1.13 (0.67–1.60) | ↑ | Animals |
| Collagen synthesis | 1.08 (0.42–1.74) | ↑ | Animals |
| Microscopic wound closure | 0.98 (0.66–1.29) | ↑ | Animals |
| Granulation tissue | 1.67 (0.54–2.79) | ↑ | Women and animals |
| Inflammatory response | −0.58 (−1.14 to −0.02) | ↓ | Women and animals |
| TGF-β1 levels | −1.68 (−2.52 to −0.83) | ↓ | Animals |
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, then twice weekly for ≥5 weeks preop, continued twice weekly for 12 months postop[1]
- All participants: vaginal hysterectomy (if uterus present) and standardized uterosacral or sacrospinous ligament suspension
- Primary outcome: composite failure at 12 months (anterior or 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 |
| Failure components | Anatomic recurrence was the most common primary failure component; a per-protocol analysis often found partial apical descent without prolapse beyond the hymen or symptoms | — | — |
| Surgeon-assessed tissue quality at surgery | Significantly better | — | p <0.05 |
| Granulation tissue after month 6 (secondary outcome) | 16/90 (18%) | 7/87 (8%) | p = 0.048; no repeat operations |
| 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: model-estimated 32.6% (estrogen) versus 26.8% (placebo); adjusted HR 1.55 (95% CI 0.90–2.66; p = 0.11)[3]
- Per-protocol analysis: similar
- Among 36-month PGI-I respondents, 75/80 (94%) in the estrogen group and 72/76 (95%) in the placebo group reported being "much or very much better"; this included 51 of 55 "surgical failures".[3]
- POP-Q, PGI-S, PFDI-20, and PFIQ-7 all improved significantly in both arms without between-group differences
- Substantial crossover at 36 months. Among 160 participants reporting estrogen use, 40/82 (49%) of the original estrogen group and 47/78 (60%) of the original placebo group were using vaginal estrogen (p = 0.15)[3]
In IMPROVE, perioperative vaginal estrogen improved surgeon-rated tissue quality at surgery, but a reduction in composite repair failure was not demonstrated at 12 or 36 months; the estimates remain imprecise.[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; the published report describes 293 participants. EVA used estriol cream 1 mg/g, 0.5 g (0.5 mg) intravaginally daily for 2 weeks, then twice weekly; treatment began 4–6 weeks preoperatively, continued through 12 months postoperatively, and paused for the first 2 postoperative weeks.[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, sexual function and reintervention did not differ significantly. Secondary outcomes favored estrogen for pelvic-floor quality of life (median PFDI-20 17 versus 25; p = 0.03) and a higher proportion reporting no discomfort or pain (EQ-5D-5L 81/105 [77.1%] versus 63/104 [60.6%]; p = 0.04).[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.[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) | 16/32 (50%) | 9/21 (43%) | 0.78 |
| UUI (bothersome at baseline) | 13/30 (43%) | 11/36 (31%) | 0.41 |
| Urinary frequency (bothersome at baseline) | 18/44 (41%) | 12/47 (26%) | 0.18 |
| Dyspareunia at preoperative assessment (sexually active participants) | 42% had dyspareunia | 48% had dyspareunia | 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 versus 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 (search to November 2017) predates IMPROVE and other 2021–2023 trials. Its 2025 update (search to April 2024) included three perioperative vaginal-estrogen trials (409 women); the postoperative-UTI estimate was uncertain (OR 0.67, 95% CI 0.36–1.26; two trials, 289 women; low-certainty evidence).[19] The later Sicilia 2025 systematic review summarizes ten RCTs and concludes that possible tissue and infection benefits remain limited by the evidence.[8][2] The 2026 Vacca meta-analysis (9 RCTs, 764 women, searched to December 2024) found improved tissue quality (standardized mean difference 0.73, 95% CI 0.16–1.30; I² 86.7%) but no difference in composite surgical success (RR 0.94, 95% CI 0.83–1.06), with a trend toward lower success in the estrogen groups.[18]
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 Vacca 2026 meta-analysis judged the UTI effect inconclusive (RR 0.75, 95% CI 0.27–2.04; I² 67.2%), with one study showing harm and two showing benefit.[18]
The Cochrane authors cautioned that contributing studies varied substantially. IMPROVE itself found no statistically significant reduction in participants with UTI (19% versus 25%; p = 0.38).[1] 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 showed that 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 versus placebo for 12 months:[12]
- Pessary continuation with satisfaction at 12 months: 181/208 (87.0%) (estrogen) versus 176/203 (86.7%) (placebo); risk difference 0.3% (95% CI −6.2 to 6.9; p = 0.92), no difference[12]
- Pessary-related adverse events reduced:
Midurethral sling outcomes
Mesh exposure — Cadish 2016 retrospective cohort
In a retrospective Kaiser Permanente cohort of 1,544 midurethral sling recipients (248 used preoperative vaginal estrogen; 627 were postmenopausal), preoperative vaginal estrogen was not associated with mesh exposure (adjusted 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 (80 completed): ultralow-dose vaginal estriol ovules 0.03 mg daily × 16 weeks (before and after surgery) versus no treatment:[14]
- Within the estriol group, Vaginal Maturation Index rose from baseline (38.1) to 43.1 pre-op (p = 0.04) and 47.8 post-op (p = 0.001)
- FSFI improved more after TOT with estriol than in controls (25.2 versus 17.2 post-op; p = 0.001)
- Mental-health QoL improved in the estriol group before surgery (p = 0.02); controls improved only after surgery
The EAU 2026 evidence summary rates local estrogen before or after synthetic midurethral sling surgery as ineffective for improving SUI surgical outcomes (level of evidence 2b), while strongly recommending vaginal estrogen for postmenopausal SUI with vulvovaginal atrophy symptoms.[22] In Caruso's unblinded TOT trial, 36/48 estriol-treated participants and 44/48 controls completed 8-week follow-up; sexual-function and quality-of-life scores improved, but sling continence and mesh exposure were not trial outcomes.[14]
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)[1] |
| EVA 2026 | Estriol cream 1 mg/g, 0.5 g/application | Daily × 2 wk | 2×/wk; planned 2-wk postop pause | 4–6 wk preop + 12 mo postop | Primary native-tissue POP repair[16] |
| 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[4] |
| Marschalek 2021[9] | Linoladiol estradiol cream 0.01% (0.10 mg/g) | Daily × 1 wk | Every 48 h × 1 wk, then twice weekly × 4 wk | 6 wk preop in the trial; exceeds EMA's current single-course 4-week maximum for Linoladiol[21] | POP repair |
Guideline positions
ACOG's POP bulletin describes limited evidence for treating or preventing prolapse with estrogen. The 2025 AUA/SUFU/AUGS GSM guideline recommends offering the option of local low-dose vaginal estrogen to patients with GSM-related vulvovaginal discomfort/irritation, dryness, and/or dyspareunia , and recommends it for patients with GSM and recurrent UTI to reduce future UTI risk . Prescribe for an individual GSM or recurrent-UTI indication when appropriate.[17][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 | Earlier review suggested benefit[10]; updated perioperative reviews report imprecise, inconsistent estimates[18][19] | Uncertain; no demonstrated reduction |
| 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 | IMPROVE 12- and 36-month estimates were imprecise | No demonstrated reduction[1][3] |
| Improves surgical success rates | IMPROVE did not demonstrate improved composite success | No demonstrated benefit[1][3] |
| Improves preoperative urinary symptoms | Inconclusive (IMPROVE ancillary) | No demonstrated benefit; effect remains uncertain[7] |
| Improves preoperative sexual function | Inconclusive (IMPROVE ancillary) | No demonstrated benefit; effect remains uncertain[7] |
| Reduces mesh exposure after sling | Retrospective cohort; 37 mesh exposures among 1,544 women | No association detected; estimate imprecise (OR 0.79, 95% CI 0.26–2.38)[13] |
Evidence Summary
| Application | Evidence level | Key source |
|---|---|---|
| Tissue quality improvement (histology, mRNA) | Small human biopsy RCT (surrogate endpoints); supporting meta-analysis mostly animal (12/14 studies) | Rahn 2014[4]; Vodegel 2022[5] |
| Composite prolapse-repair failure (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] |
| Composite prolapse-repair failure (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.[1][3]
- Counsel that improved repair success was not demonstrated.[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.[20]
- 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, and patient preference; follow current product-specific contraindications and warnings. Reassess treatment response; long-term treatment and follow-up may be required.[17]
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.
17. Kaufman MR, Ackerman AL, Amin KA, et al. "The AUA/SUFU/AUGS Guideline on Genitourinary Syndrome of Menopause." J Urol. 2025;214(3):242–250. doi:10.1097/JU.0000000000004589
18. Vacca L, Pierro M, Foresta A, et al. "From tissue to outcome: how perioperative vaginal estrogen transforms prolapse surgery results: a systematic review and meta-analysis of clinical evidence and outcomes." Climacteric. 2026;29(4):516–526. doi:10.1080/13697137.2026.2671751
19. Shahid U, Haya N, Baessler K, et al. "Perioperative interventions in pelvic organ prolapse surgery." Cochrane Database Syst Rev. 2025;2025(7):CD013105. doi:10.1002/14651858.CD013105.pub2
20. Novo Nordisk Inc. VAGIFEM (estradiol vaginal inserts) prescribing information. DailyMed. Full label.
21. European Medicines Agency. "Estradiol-containing (0.01% w/w) medicinal products for topical use: four-week limit for use of high-strength estradiol creams confirmed." EMA referral. 2020. Official safety notice.
22. European Association of Urology. "EAU Guidelines on Non-neurogenic Female LUTS: Disease Management." EAU Guidelines. 2026. Full guideline.