What evidence is there for use of estradiol cream or conjugated estrogen in gynecologic (ie. hysterectomy) and female urology procedures?

Comment by InpharmD Researcher

Available evidence assessing the use of estradiol cream and conjugated estrogen in gynecologic and urological procedures, including hysterectomy and pelvic organ prolapse surgery, suggests mixed outcomes. Studies commonly evaluate conjugated equine estrogens when investigating use of topical vaginal therapy; however, perioperative data specifically assessing its use in surgery suggest limited benefit (see Tables 1-2). While topical estrogens may improve vaginal tissue quality and alleviate symptoms of vaginal atrophy, their impact on surgical outcomes (e.g., reducing mesh exposure and prolapse recurrence), remains inconsistent and unclear.

Background

Guidance from the American College of Obstetricians and Gynecologists (ACOG), in collaboration with the American Urogynecologic Society (AUS), provides detailed recommendations on the management of complications associated with mesh used for stress urinary incontinence (SUI) and pelvic organ prolapse (POP). Management of mesh-related complications in pelvic floor surgery involves a spectrum of approaches that include observation, physical therapy, medications, and surgical intervention. For symptomatic women, a trial of vaginal estrogen (no specific formulation or strengths discussed) may be considered for small exposures (less than 0.5 cm), with a trial period of 6-12 weeks. Although topical estrogen may improve or resolve mesh exposure, supporting evidence is limited. A multicenter study highlighted that 60% of women with mesh complications required two or more interventions, with the first intervention being surgical in about half of the cases. Such procedures are complex and should be handled with caution, emphasizing the importance of referral to surgeons familiar with these repairs if the original procedures or subsequent management issues are beyond the operating surgeon's experience. [1]

Vaginal mesh exposure following a midurethral sling procedure occurs in approximately 1-2% of cases. For asymptomatic patients with type 1 mesh, expectant management, with or without the application of topical estrogen, may be appropriate, as some small case reports indicate that spontaneous reepithelialization is possible. Should topical estrogen fail, surgical options include excising the edges of the vaginal incision and reapproximating them for a tension-free closure, though few success rates are published for primary reclosure. The procedure is considered low-risk. In cases where both expectant management and primary reclosure fail, and if the patient wishes to preserve the sling, options like full-thickness autologous graft transposition or Martius graft transposition have been documented, although data to guide these decisions is sparse. If preservation methods are unsuccessful and the patient remains symptomatic, sling excision may be performed, albeit with a risk of recurrent stress urinary incontinence (SUI). Complete removal of the mesh is usually unnecessary. [1]

A 2023 randomized trial (IMPROVE) investigated the efficacy of perioperative vaginal estrogen as an adjunct to native tissue vaginal apical prolapse repair. Conducted across three United States tertiary clinical sites, the trial enrolled 206 postmenopausal women with symptomatic anterior and apical vaginal prolapse who were candidates for surgical repair. Participants were randomized in a 1:1 ratio to receive either conjugated estrogen cream (0.625 mg/g) or a visually identical placebo cream. The intervention was administered intravaginally nightly for two weeks, then twice weekly for at least five weeks preoperatively, continuing at the same frequency for 12 months postoperatively. Standardized surgical procedures were performed by masked surgeons; midurethral slings (MUS) were performed in 57% of both estrogen and placebo patients, while hysterectomies were performed in 82% and 85% of estrogen and placebo patients, respectively. The 12-month incidence of surgical failure was 19% in the vaginal estrogen group and 9% in the placebo group, with an adjusted hazard ratio (HR) of 1.97 (95% confidence interval [CI] 0.92 to 4.22). No statistically significant difference in surgical success was observed between treatment arms. Despite better intraoperative assessments of vaginal tissue quality in participants receiving estrogen, this did not translate into improved surgical outcomes. However, among participants with bothersome vaginal atrophy symptoms at baseline, those in the estrogen group demonstrated significantly greater improvement in atrophy-related symptoms (adjusted mean difference -0.87; 95% CI -1.67 to -0.07; p= 0.003). Urinary tract infections occurred at a similar frequency between groups, while increases in postoperative granulation tissue were more frequently observed in the estrogen group. These findings suggest that while perioperative vaginal estrogen enhanced vaginal tissue quality and alleviates atrophic symptoms, it did not reduce prolapse recurrence following native tissue transvaginal repair. [2]

A 2015 retrospective cohort study evaluated whether the preoperative use of vaginal estrogen influences the risk of mesh exposure following synthetic MUS placement. The investigation included 1,544 women who underwent MUS insertion in 2010. Preoperative estrogen use was determined based on filled prescriptions within 45 days before surgery or documented use in preoperative evaluations. Findings indicated that 16.1% (n= 248) of the cohort had used vaginal estrogen preoperatively, primarily in the form of estrogen cream (90.3%). Mesh exposure occurred in 2.4% (n= 37) of patients, with nearly half (n= 19) requiring surgical revision. Median time to mesh exposure diagnosis was 56 days postoperatively. Multivariate analysis demonstrated no statistically significant association between preoperative vaginal estrogen use and mesh exposure risk (odds ratio [OR] 0.79; 95% CI 0.26 to 2.38; p= 0.67). Additionally, other evaluated factors (e.g., smoking, menopausal status, diabetes) were not associated with mesh exposure. Despite inherent limitations of retrospective study design and sample size constraints, the findings suggest that preoperative vaginal estrogen use does not mitigate the risk of mesh exposure following MUS placement. [3]

A 2010 analysis of a 12-month, double-blind, randomized, parallel-therapy trial compared the cardiovascular and metabolic effects of medroxyprogesterone acetate (MPA) and conjugated equine estrogen (CEE) as monotherapy in 33 premenopausal women undergoing hysterectomy with bilateral ovariectomy. Participants received either MPA 10 mg/day (n= 18) or CEE 0.6 mg/day (n= 15) starting immediately post-surgery. After 12 months, women assigned to CEE exhibited significantly greater increases in CRP (p= 0.01) and reductions in serum albumin (p<0.0005) versus those receiving MPA, suggesting a pro-inflammatory effect of estrogen therapy. The MPA group experienced significantly lower increases in BMI (p= 0.04), triglycerides (p= 0.003), and sex hormone-binding globulin (SHBG; p<0.0005), while CEE use was associated with higher HDL (p<0.0005) and total testosterone (p= 0.003) levels. Despite these differences, bioavailable testosterone levels, estimated using the free androgen index, remained similar between groups. Additionally, BMI and CRP demonstrated a positive correlation in the MPA group (p<0.005), an association that was absent in the CEE group. These findings indicate that MPA may exert a more favorable effect on inflammation, lipid metabolism, and body composition compared to CEE monotherapy in surgically menopausal women, warranting further research in larger controlled trials. [4]

A 2006 controlled trial (Table 1) evaluated the benefit and safety of a 28-day transdermal 17-beta estradiol regimen in postmenopausal women undergoing vaginal hysterectomy. 269 participants were divided into two groups: one receiving a transdermal estrogen hormone replacement therapy (TEHRT) regimen of 50 mcg/day 17-β estradiol for 14 days preoperatively and 14 days postoperatively, and a control group receiving vaginal estrogen hormone replacement therapy (VEHRT) in the form of 0.625 mg/day conjugated estrogen cream (Premarin) for 14 days preoperatively. Findings demonstrated significantly improved wound healing parameters in the TEHRT group, including reduced pain, swelling, vaginal discharge, and wound dehiscence (p<0.001). Postoperative infection markers, such as leukocyte count and fever incidence, were also lower in the TEHRT group (p<0.01). On follow-up, patients in the TEHRT group exhibited better anatomical outcomes, with a higher frequency of stage 0 apical prolapse (p <0.05) and greater total vaginal length preservation (p<0.05). The endometrial evaluation revealed a modest estrogenic effect in TEHRT recipients, with an increased frequency of an endometrial thickness between 2 and 4 mm (p<0.05); however, no cases of complex hyperplasia, atypical hyperplasia, or carcinoma were observed in either group. The findings suggest that a 28-day transdermal 17-β estradiol regimen offers superior postoperative recovery while maintaining an acceptable safety profile concerning endometrial health. [5]

References:

[1] American College of Obstetricians and Gynecologists. Management of Mesh and Graft Complications in Gynecologic Surgery. Female Pelvic Med Reconstr Surg. 2017;23(3):171-176. doi:10.1097/SPV.0000000000000425
[2] 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. JAMA. 2023;330(7):615-625. doi:10.1001/jama.2023.12317
[3] Cadish LA, West EH, Sisto J, Longoria T, Bebchuk JD, Whitcomb EL. 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
[4] Kalyan S, Hitchcock CL, Sirrs S, Pudek M, Prior JC. Cardiovascular and metabolic effects of medroxyprogesterone acetate versus conjugated equine estrogen after premenopausal hysterectomy with bilateral ovariectomy. Pharmacotherapy. 2010;30(5):442-452. doi:10.1592/phco.30.5.442
[5] Vesna A, Neli B. Benefit and safety of 28-day transdermal estrogen regimen during vaginal hysterectomy (a controlled trial). Maturitas. 2006;53(3):282-298. doi:10.1016/j.maturitas.2005.05.012

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What evidence is there for use of estradiol cream or conjugated estrogen in gynecologic (ie. hysterectomy) and female urology procedures?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-2 for your response.


 

Benefit and safety of 28-day transdermal estrogen regiment during vaginal hysterectomy (a controlled trial)

Design

Randomized, controlled, open-label trial

N= 269

Objective

To assess the benefit and safety of a 28-day transdermal 17-estradiol regimen during vaginal hysterectomy compared to a 14-day preoperative vaginal conjugated estrogen regimen

Study Groups

TEHRT group (n= 119)

VEHRT group (n= 150)

Inclusion Criteria

At least 1-year long postmenopausal period; presence of genital prolapse requiring vaginal hysterectomy

Exclusion Criteria

Presence of contraindications for HRT such as previous history of breast cancer, biliar calculosis, or significant coagulation disorders

Methods

Participants were divided into two groups: the TEHRT group received 28-day transdermal 17-estradiol 50 mcg/day, 14 days before and after operation; the VEHRT group received 14-day preoperative vaginal conjugated estrogen (Premarin) 0.625 mg/day. Evaluations included endometrial thickness, wound healing, infection, and recurrence of organ prolapse.

Duration

January 1998 to June 2003

Outcome Measures

Primary: Wound healing, infection rates, recurrence of organ prolapse

Secondary: Endometrial thickness, morphological changes

Baseline Characteristics  

Estradiol (n= 119)

Premarin (n= 150)

Age, years

62.5 ± 12.8 64.3 ± 14.2

Duration of postmenopausal period, years

14.2 ± 3.3 16.1 ± 3.8

Parity

3.6 ± 2.1 3.3 ± 2.0

Body mass index, kg/m2

24.6 ± 3.0 25.1 ± 3.2
Results  

Estradiol (n= 119)

Premarin (n= 150) p-value

Pain symptoms in postoperative period

42/119 (35.3%) 93/150 (62%) 0.001

Fetid vaginal discharge in postoperative period

8/119 (6.7%) 33/150 (22%) 0.001

Swelling and crusting in the first seven postoperative days

9/119 (7.6%) 36/150 (24%) 0.001

Clearly visible wound opening on suture sites in the first postoperative week

2/119 (1.7%) 19/150 (12.7%) 0.01

Patient assessment of outcome at the first (4 week) control - Satisfied

112/119 (94.1%) 105/150 (70%) 0.001
Adverse Events

No significant differences in occurrence of more thickened endometrium and more significant morphological changes between the groups. No complex hyperplasia, atypical hyperplasia, or endometrial carcinoma was observed in any patients.

Study Author Conclusions

The 28-day transdermal 17-estradiol regimen seems to be a safe and effective procedure for improving wound healing and reducing infection rates during vaginal hysterectomy.

Critique

The study provides valuable insights into the benefits of transdermal estrogen therapy in surgical settings, but the lack of randomization and potential selection bias due to the non-randomized allocation of patients to treatment groups may limit the generalizability of the findings.

 

References:

Vesna A, Neli B. Benefit and safety of 28-day transdermal estrogen regimen during vaginal hysterectomy (a controlled trial). Maturitas. 2006;53(3):282-298. doi:10.1016/j.maturitas.2005.05.012

Effects of preoperative vaginal estrogen therapy for the incidence of mesh complication after pelvic organ prolapse surgery in postmenopausal women: is it helpful or a myth? A 1-year randomized controlled trial
Design

Randomized noninferiority single-surgeon study

N= 186

Objective

To compare the effects of preoperative vaginal estrogen (VE) and non-VE therapy for the incidence of mesh exposure in postmenopausal women after transvaginal pelvic reconstructive surgery (PRS) with mesh

Study Groups

VE group (n= 93)

Non-VE group (n= 93)

Inclusion Criteria

Aged 50 to 75 years; postmenopausal; diagnosed with uterine prolapse stage 3 or 4 combined with anterior vaginal wall prolapse stage 3 or 4; referred for transvaginal PRS with mesh

Exclusion Criteria

Received oral or transdermal estrogen therapy within 1 year; contraindication for local estrogen application; any type of cancer; inability to tolerate laparoscopic procedures; history of anti-incontinence or prolapse surgical repair; need for concomitant surgery

Methods

Participants were randomized to receive 0.5 g promestriene cream transvaginally twice a week for 6 weeks before PRS with mesh (VE group), or to undergo PRS with mesh 6 weeks after enrollment without pharmacologic preparation (non-VE group). The primary outcome was the occurrence of mesh exposure within 1 year. 

Duration

August 2013 to May 2014

Outcome Measures

Primary: Occurrence of mesh exposure within 1 year

Secondary: Anatomic success, Patient Global Impression of Change, improvement in quality of life and sexual function, complications

Baseline Characteristics  

VE group (n= 93)

Non-VE group (n= 93)
Age at diagnosis, years (range)

66 (50-75)

65 (51-74)
BMI, kg/m(range)

24.2 (18.4-28.9)

24.5 (17.7-30.0)
Gravidity (range)

3 (1-5)

3 (1-4)
Parity (range)

2 (1-3)

2 (1-3)

POP-Q stage

Anterior stage: 3 or 4

Apical stage: 3 or 4

Posterior stage: 1

Posterior stage: 2

Posterior stage: 3 or 4

 

93 (100%)

93 (100%)

25 (26.9%)

47 (50.5%)

21 (22.6%)

 

93 (100%)

93 (100%)

16 (17.2%)

57 (61.2%)

20 (21.5%)

Symptom of vaginal bulging

85 (91.4%) 82 (88.2%)

Previous surgery for prolapse repair

0% 0%

No urgency urinary incontinence, no

0% 0%

Objective stress urinary incontinence, no

0% 0%

Occult stress urinary incontinence, no

4 (4.3%) 6 (6.5%)

Estrogen therapy used within 1 y, no

0% 0%

Estrogen therapy used 2-3 y earlier

3 (3.2%) 2 (2.2%)
Sexually active

19 (20.4%)

21 (22.6%)

PFIQ-7 (range)

52 (14-176) 57 (14-195)

PISQ-12 (range)*

25 (14-32) 26 (16-32)

Abbreviations: BMI, body mass index; PFIQ-7, Pelvic Floor Impact Questionnaire Short Form; PISQ-12, Short-Form Pelvic Organ Prolapse/Urinary Incontinence Sexual
Questionnaire; POP-Q, pelvic organ prolapse quantification; VE, vaginal estrogen.

*PISQ-12 was only collected for participants who were sexually active at baseline (n= 19 for VE group vs n= 21 for non-VE group)

Results Endpoint

VE group (n= 93)

Non-VE group (n= 93) p-value
Mesh exposure rate at 12 months

15 (16.1%)

12 (12.9%)  0.024
Anatomic success rate at 12 months

100%

98.9% 1.000
Subjective satisfaction rate at 12 months

97.8%

97.8% 0.613
PFIQ-7 change rate 

97.8%

95.7%
PISQ-12 change rate 

15.8%

14.3% > 0.05 
Adverse Events

Approximately 44.6% of all women experienced complications. The most common complications were vaginal, occurring in 32.3% and 34.4% of women receiving and not receiving VE therapy, respectively. Skin and mucous events were more frequent in the VE group (p= 0.030). 

Study Author Conclusions

In postmenopausal women with severe POP who underwent transvaginal PRS with mesh, non-VE therapy before surgery was noninferior to VE therapy regarding mesh exposure rate within 1 year of follow-up.

Critique

The study was well-designed as a randomized controlled trial with a clear objective and adequate sample size. However, the single-center design and lack of blinding may limit the generalizability of the findings. Additionally, the study only evaluated preoperative VE use, not postoperative, which could potentially have different outcomes.

References:

Sun Z, Zhu L, Xu T, Shi X, Lang J. Effects of preoperative vaginal estrogen therapy for the incidence of mesh complication after pelvic organ prolapse surgery in postmenopausal women: is it helpful or a myth? A 1-year randomized controlled trial. Menopause. 2016;23(7):740-748. doi:10.1097/GME.0000000000000614