Introduction
Women who are heading to the menopause phase will experience various health problems [1]. Pelvic floor dysfunction is one of the causes of morbidity that can reduce women’s quality of life. Pelvic floor dysfunction has a high prevalence, both in developing and developing countries, although the main cause is unknown [2]. It is estimated that 11% of women over the age of 80 will undergo pelvic reconstructive surgery and one third of women with pelvic organ prolapse undergo at least one surgical procedure [3].
Pelvic organ prolapse (POP), also known as urogenital prolapse, is a descending of the pelvic organs causing protrusion of the vagina, uterus or both. This condition can damage the anterior, posterior vaginal walls, and the uterus or vaginal crest, which generally appears as a combination of the above conditions. In 1997, a study revealed that women with a life expectancy of 79 years had an 11—12% chance of undergoing surgery for cases of prolapse or incontinence, with a re-operative incidence of 29.2%. Pelvic organ prolapse is the most common indication for hysterectomy in postmenopausal women and accounts for 15—18% of all procedures in all age groups. As women in the current generation adopt an active lifestyle more than older women, it seems that women seeking treatment for prolapse cases will tend to increase. It has been projected that over the next 30 years, the number of women seeking treatment for pelvic floor disorders will double [4]. Although the mechanism of pelvic organ prolapse in women and the factors that lead to failure of surgical repair are not fully understood. There is some evidence to support that structural abnormalities of the connective tissue are a predisposing factor [2].
Management of POP is done if there is protrusion, urinary, bowel, or sexual dysfunction and other symptoms associated with POP. Patients with asymptomatic POP usually do not require treatment. Conservative or surgical management is reserved for symptomatic patients, and treatment options depend on patient preference. Conservative management is appropriate for patients who are at high risk of complications and recurrence after surgical treatment or who refuse to undergo surgical intervention. Treatment options include pessary insertion, pelvic floor muscle training, hormone therapy and others [5]. Conservative and surgical management may be appropriate depending on the patient’s age, desire for future fertility and coitus function, severity of symptoms, and accompanying medical problems. Most women can successfully fit with a vaginal pessary. The surgical options available are reconstructive hip surgery with or without mesh augmentation and obliterative surgery [6].
However, in treatments such as the use of a pessary or preparation for surgery, other treatments are needed to support it. The abundance of estrogen receptors in the urogenital tract explains why the natural reduction of endogenous estrogen, a hallmark of menopause, can cause or potentiate pelvic organ involvement. Low-dose vaginal estrogen therapy is the preferred and most effective treatment in some urogenital-related cases. Vaginal estrogen therapy is superior to non-hormonal therapy in improving symptoms in patients with two or more complaints [7]. Impaired wound healing can lead to recurrence of prolapse after hip reconstructive surgery, and that estrogen may serve as an adjunct to surgical repair. Sinuses where estrogen receptors are expressed during development and in adult tissues of the vagina, urethra, bladder, and surrounding pelvic floor muscles. This study aims to systematically review the role of estrogen in supporting pelvic organ prolapse treatment.
Methods
Study design and search strategy
This systematic review follows the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Reviews are well organized but not yet registered. Data was collected from August 2022. Search for English articles in five databases, namely Google Scholar, ScienceDirect, PubMed, ProQuest and Scopus. Search using keywords included in table 1. The management of pelvic organ prolapse studied in this study was the use of pessaries and surgery.
Table 1. Keywords
|
Type of treatment |
Keywords |
|
Pessary |
«pelvic organ prolapse» AND «pessary» and «estrogen» OR «estriol» |
|
Surgery |
«pelvic organ prolapse» AND «surgery» and «estrogen» OR «estriol» |
Study selection
The inclusion criteria applied in selecting articles were cohort and randomized controlled trials, discussed the role of estrogen in pessary use and surgery in pelvic organ prolapse treatment, and the study was conducted last ten years from 2012 to 2022. The exclusion criteria for this study were case reports, animal studies, letters to editors, study reviews, preprint, and abstracts without full text.
Data collection process
The authors performed title and/or abstract screening independently of the included articles using standard Microsoft Excel forms. The data obtained were combined in one folder and then an assessment was carried out. Each author analyzed all existing manuscripts, and then the results were compared with each other. A third external collaborator was consulted to address disagreements in consensus.
Effect measures and study risk of bias assessment
Authors conducted a risk of bias assessment study using critical appraisal tools. The authors performed title and/or abstract screening independently of the included articles using standard Microsoft Excel forms. In assessing the agreement of incoming articles, the researcher used the Cohen’s Kappa Consistency Test. In addition, consensus is also carried out with the assistance of a third person if no agreement is found. Researchers conducted a risk of bias assessment study with the help of critical appraisal tools. The research quality in this review was analyzed using critical appraisal tools, namely the Mixed Methods Appraisal Tool (MMAT) version 2018. The MMAT is a critical appraisal tool that is designed for the appraisal stage of systematic mixed studies reviews, i.e., reviews that include qualitative, quantitative and mixed methods studies [8]. The results of the analysis are presented in table 1.
Data abstraction and synthesis
The study selection process was through a review of the inclusion and exclusion criteria. As suggested in a systematic review of the literature, the analysis in this study was based on the findings of each study. The steps started from extracting the relevant results, sorting, and examining them to identify sub-themes and themes. The type of synthesis used is in the form of qualitative synthesis. The data are arranged in table 2 contains the characteristics of research involve (1) authors, year, country, (2) study type, (3) number of samples, (4) criteria, (5) types of estrogen and route of administration, (6) outcome, (7) adverse effect and (8) finding [9—15].
Results
Screening and article quality
The results of the search for articles through the database using keywords were found as many as 271 articles. From that number of articles, 268 were screened and excluded which did not meet the inclusion and exclusion criteria. Full text articles assessed for eligibility were 10. A total of 7 articles were included in the qualitative analysis. The article search process is included in the PRISMA flow chat in figure. The quality results of the study indicate that all articles were in the moderate category. The results of the assessment are in table 2.
Prisma Flow Chart.
Table 2. Quality Assessment using MMAT
|
Study design and studies |
Assessment criteria |
Total Score |
||||
|
Quantitative non randomized |
Are the participants representative of the target population? |
Are measurements appropriate regarding both the outcome and intervention (or exposure)? |
Are there complete outcome data? |
Are the confounders accounted for in the design and analysis? |
During the study period, is the intervention administered (or exposure occurred) as intended? |
|
|
S. Bulchandani et al., 2015, UK [9] |
Y |
Y |
Y |
Y |
N |
4 |
|
S. Dessie et al., 2016, USA [10] |
Y |
N |
Y |
N |
Y |
3 |
|
Quantitative randomized controlled trials |
Is randomization appropriately performed? |
Are the groups comparable at baseline? |
Are there complete outcome data? |
Are outcome assessors blinded to the intervention provided? |
Did the participants adhere to the assigned intervention? |
|
|
K. Chiengthong et al., 2021, Thailand [11] |
Y |
Y |
Y |
N |
Y |
4 |
|
S. de Albuquerque Coelho et al., 2021, Brazil [12] |
Y |
Y |
Y |
N |
Y |
4 |
|
D. Rahn et al., 2014, USA [13] |
Y |
Y |
Y |
Y/N |
Y |
4.5 |
|
C. Vaccaro et al., 2013, Cincinnati [14] |
Y |
Y |
Y |
N |
Y |
4 |
|
M. Marschalek et al., 2021, Austria [15] |
Y |
Y |
Y |
Y/N |
Y |
4.5 |
Samples
A total of 495 postmenopausal women who used pessaries and experienced pelvic organ prolapse were included in the study. Women who will undergo surgery related to pelvic organ prolapse as many as 192 women were also included in the study. Research with pessaries all involve women who have menopause. Not all studies explain the minimum use of pessaries in the respondents they include in the study. There is a study that provides the criteria for respondents to use at least 3 months of pessary use. The number of samples is included in table 3.
Table 3. Research Characteristics
|
Authors, year, country |
Study type |
Number of samples |
Criteria |
Types of estrogen and route of administration |
Outcome |
Adverse effect |
Finding |
|
Pessary |
|||||||
|
K. Chiengthong et al., 2021, Thailand [11] |
A single-center, open-label, randomized, parallel study |
Seventy-eight women were included and randomized to two groups (39 women per group) |
The inclusion criteria were menopausal Thai women with symptomatic pelvic organ prolapse who were capable of completing the questionnaire and had undergone successful pessary fitting |
Intravaginal estriol 0.03 mg plus Lactobacillus acidophilus 100 million viable cell vaginal tablets or have no treatment |
The Amsel criteria, normal flora index, visual analog scale, Thai version of the ICIQ-VS (International Consultation on Incontinence Questionnaire-Vaginal symptoms) questionnaire, vaginal abrasions and vaginal bleeding were evaluated at entry and at 2- and 14-week follow-up |
NA |
Normal flora index was significantly different at 2-week follow up [8 (6.3) vs. 5 (6.0), p=0.032]. There was no significant difference in the visual analog scale, Thai version of the ICIQ-VS, vaginal abrasions and vaginal bleeding between the 2- and 14-week follow-ups. no benefit of intravaginal estrogen in reducing bacterial vaginosis, vaginal abrasions, vaginal bleeding and pain in postmenopausal women using a vaginal pessary for pelvic organ prolapse treatment |
|
S. Bulchandani et al., 2015, UK [9] |
Prospective cohort study |
120 postmenopausal women using support pessaries for prolapse |
Women attending the urogynaecology clinic for a pessary change. The urogynaecology nurse specialist or doctor |
The vaginal estrogen use was recorded for current frequency of usage, which ranged from 3 months to 1 year. The type of formulation used was as per patient choice and included either Oestriol cream 0.1%, Oestradiol 10 mcg pessaries or Oestradiol rings 1.94 mg being used between once a week to twice a week application or as required |
The level of discomfort during pessary change (visual analogue scale for pain), discharge, bleeding and infection ulceration, discharge, pain, bleeding and infection and history of using VOT |
NA |
There were no statistically significant differences in complications with or without vaginal estrogen use, although the trend was higher amongst non-users. The ‘non-ring’ sub-group not using vaginal estrogen had a higher risk of vaginal ulceration, bleeding and discharge. Postmenopausal women may have lesser complications when using vaginal estrogen with a support pessary for prolapse, particularly with pessaries other than the ring |
|
S. Dessie et al., 2016, USA [10] |
Retrospective cohort study |
Data from 199 women were included; 134 used vaginal estrogen and 65 did not |
Women who underwent a pessary fitting from 1 January 2007 through 1 September 2013 at one institution; participants were identified by billing code and were eligible if they were post-menopausal and had at least 3 months of pessary use and 6 months of follow-up |
NA |
Our primary outcome was development of erosions as defined by the provider’s documentation of an erosion in the patient medical record; secondary outcomes included discontinuation of pessary use, reason for discontinuation, increased vaginal discharge, and vaginal bleeding |
NA |
Women who used vaginal estrogen had a longer median follow-up time (29.5 months) compared with women who did not (15.4 months) and were more likely to have at least one pessary check (98.5% vs 86.2%, P<0.001). Those in the estrogen group were less likely to discontinue using their pessary (30.6% vs 58.5%, P<0.001) and less likely to develop increased vaginal discharge than women who did not [hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.17—0.58]. Vaginal estrogen was not protective against erosions (HR 0.93, 95% CI 0.54—1.6) or vaginal bleeding (HR 0.78, 95% CI 0.36—1.7). Women who used vaginal estrogen exhibited a higher incidence of continued pessary use and lower incidence of increased vaginal discharge than women who did not |
|
S. de Albuquerque Coelho et al., 2021, Brazil [12] |
A parallel, single-blinded, randomized, controlled trial |
98 women with pelvic organ prolapse (POP) (stage 3/4) |
Symptomatic postmenopausal women with pelvic organ prolapse (POP) |
The estrogen group was prescribed a topical estrogen cream (10 mg/g promestriene cream, 0.5 g 3 times per week) |
Their vaginal symptoms at the baseline, after 3 months, and after 6 months, and a physical examination and vaginal sampling for microbiological analysis were done |
No |
Regarding the presence of complications, the presence of erosion was 10% in the control group, but there was no significant difference between the groups (p=0.175) after 6 months. Bacterial vaginosis (BV) was more prevalent in the control group, according to the Nugent (p=0.007) and Amsel (p=0.014) criteria. Urinary urgency and increased urinary frequency were significantly improved in the estrogen group after 6 months. Conclusion There was no evident benefit related to complications such as ulcerations, itching, and vaginal discharge/odor from the use of vaginal estrogen in POP women using pessaries |
|
Underwent surgery |
|||||||
|
D. Rahn et al., 2014, USA [13] |
A randomized trial |
Fifteen women per group (n 30 total) were randomized; 13 per group underwent surgery |
Postmenopausal women with a uterus and symptomatic anterior and/or apical prolapse at stage 2 or greater participated in the study |
Estrogen (Premarin) or placebo cream for 6 weeks preoperatively was the intervention. Premarin cream (0.625 mg drug per 1 g cream |
Full-thickness anterior apical vaginal wall biopsies were obtained at the time of hysterectomy and analyzed for mucosa and muscularis thickness, connective tissue synthesis, and degradation. Serum levels of estrone and 17-estradiol were analyzed at baseline and the day of surgery using highly sensitive liquid chromatography-tandem mass spectrometry |
NA |
Vaginal estrogen application for 6 weeks preoperatively increased synthesis of mature collagen, decreased degradative enzyme activity, and increased thickness of the vaginal wall, suggesting this intervention improves both the substrate for suture placement at the time of surgical repair and maintenance of connective tissue integrity of the pelvic floor |
|
S. Vaccaro et al., 2013, Cincinnati [14] |
A Randomized Controlled Trial |
Forty-two women with atrophic vaginitis and stage greater than or equal to 2 prolapse were enrolled |
Inclusion criteria were postmenopausal women with clinical atrophic vaginitis and posthysterectomy POP (Stage Q2 on POP quantification) desiring surgical management within 2 to 12 weeks from enrollment. Because o multiple surgeon and patient variables that contributed to a final surgery date determination, the time from enrollment to surgery was restricted to 2 to 12 weeks. Postmenopausal status was defined as either natural (912 months since last menses and age 55 years and older) or surgical (history of bilateral salpingo-oophorectomy and age 45 years and older) |
In this assessor-blinded randomized controlled trial comparing daily vaginal estrogen cream use for 2 to 12 weeks preoperatively versus no intervention. Participants were randomized to 3 arms using a 1:1:1 ratio to receive vaginal cream (0.5 or 1.0 g) or control (no intervention) |
Citology (VMI) and histology |
Maginal burning and/or pain |
After a mean 7 (3) weeks of use, the vaginal maturity index increased 15.5% in the treatment group and declined 1.5% in the control group (P G 0.001). The vaginal epithelial thickness was 339 (96) Km in the treatment group compared to 302 (119) Km (P=0.275) in the controls. Conclusions: Preoperative vaginal estrogen application for 2 to 12 weeks restores vaginal cytology to premenopausal levels, but does not increase vaginal epithelial thickness in women with prolapse |
|
M. Marschalek et al., 2021, Austria [15] |
A randomised controlled double-masked, placebo-controlled, multicentre study |
Out of 120 women randomised, 103 (86%) remained for the final analysis. 51 local estrogen vs 52 control |
Postmenopausal women with symptomatic pelvic organ prolapse and planned surgical prolapse repair. Postmenopausal women with symptomatic POP and planned surgical prolapse repair were eligible participants |
Women were randomly assigned local estrogen cream or placebo cream 6 weeks preoperatively. Linoladiol cream or placebo cream. The active ingredient of the Linoladiol estradiol-containing emulsion is 0.10 mg of estradiol in 1 g of cream |
The primary outcome was differences in subjective prolapse-associated complaints after 6 weeks of treatment prior to surgery, assessed with the comprehensive German pelvic floor questionnaire. Secondary outcomes included differences in other pelvic floor-associated complaints (bladder, bowel or sexual function) |
No |
These results demonstrate that preoperative locally applied estrogen does not ameliorate prolapse-associated symptoms in postmenopausal women with symptomatic pelvic organ prolapse |
Estrogen administered in pessary use
Giving estrogen in the form of tablets or creams with varying doses. The doses given were intravaginal estriol 0.03 mg plus Lactobacillus acidophilus 100 million viable cell vaginal tablets, oestriol cream 0.1%, oestradiol 10 mcg pessaries or oestradiol rings 1.94 mg, topical estrogen cream (10 mg/g promestriene cream). The duration of use varies from a count per week or twice a week application to three times per week, other studies from 3 months to 1 year. Estrogens given to the use of pessaries are listed in table 3.
Estrogen given at the time of surgery
Estrogen is given mostly 6 weeks before surgery, but some start giving it from 2 weeks to 12 weeks. Premarin cream (0.625 mg of drug per 1 g of cream, vaginal cream (0.5 or 1.0 g) or Linoladiol cream (0.10 mg of estradiol in 1 g of cream). Estrogens given at the time of surgery are listed in table 3.
Finding
The results showed various conclusions. Although the normal flora indices differed significantly, there was no benefit of intravaginal estrogen in reducing bacterial vaginosis, vaginal abrasions, vaginal bleeding and pain in postmenopausal women using vaginal pessaries for the treatment of pelvic organ prolapse. But there are studies that have found that postmenopausal women may have lower complications when using vaginal estrogens with a supportive pessary for prolapse, especially with non-ring pessaries and are less likely to stop wearing pessaries because they are less likely to have increased vaginal discharge. Other studies have argued in terms of reducing vaginal discharge symptoms, ie although bacterial vaginosis was more common in the control group, there was no clear benefit associated with complications such as ulceration, itching, and vaginal discharge/odor from vaginal estrogen use in POP women taking pessaries. In women undergoing surgery, vaginal estrogen application for 6 weeks before surgery increased mature collagen synthesis, decreased degradative enzyme activity, and increased vaginal wall thickness. The vaginal maturity index may increase the initial 3 weeks with 2 to 12 weeks of use. This would return vaginal cytology to premenopausal levels, but not increase vaginal epithelial thickness in women with prolapse. However, estrogens applied locally before surgery do not improve prolapse-related symptoms in postmenopausal women with symptomatic pelvic organ prolapse. Finding is presented in table 3.
Adverse effect
Not all studies examine the adverse effects of estrogen use. Two studies found no adverse effect. One study found an adverse effect, namely vaginal burning and/or pain. Adverse effects are presented in table 3 [14].
Discussion
This study found that most studies are contradictory but there is a potential benefit of using estrogen in women who use pessaries and women who will undergo surgery. The benefits provided vary. Depending on the specific needs of the patient, individualization of different types and number of treatments is possible [16]. Another study related to vaginal atrophy, a randomized controlled trial, found that local administration of low-dose vaginal estrogen was effective and well tolerated for treating vaginal atrophy. All low-dose vaginal estrogen products approved in the United States for the treatment of vaginal atrophy are as effective as the labeling recommended doses. The choice of therapy should be guided by clinical experience and patient preferences [17].
Topical estrogen is an effective therapy in the management of vaginal atrophy and reduces complaints such as urinary incontinence and overactive bladder [18]. Estrogen can inhibit the process of pelvic organ prolapse by inhibiting the level of Mfn2, as well as promoting the expression of procollagens and proliferation of fibroblasts [19]. Localized intravaginal estrogen in postmenopausal women by any delivery system (oestrogen-containing cream, tablet, or ring) is known to lower vaginal pH, increase blood flow, increase tissue adherence, and increase vaginal cell maturity. In ovariectomized guinea pigs, preoperative systemic estrogen (with continued postoperative use) resulted in significant growth, smooth muscle gain, increased vaginal thickness, increased distensibility without compromising maximal strength at failure, and increased total collagen [20].
Estrogen is considered to provide significant benefits with low risk so that in this study it was also found that about 1 person only got the adverse effect of vaginal burning or pain. Local application of estrogen has been shown to relieve these symptoms and improve quality of life for these women. In addition, local estrogen therapy may have a favorable effect on sexuality, urinary tract infections, vaginal surgery, and incontinence [9]. This study is still not able to decipher the right dose for the use of estrogen and the number of studies is limited. Future research is expected to be able to analyze the right dose so that the best outcome is found.
Conclusion
The use of estrogen in the management of surgical preparation and the use of pessaries shows varying results, but there is a possibility of an effect of the use of estrogen. Further research is needed to ensure accurate dosing and effective timing to produce the best outcome.
Source of funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of interest. There are no conflicts of interest.
Acknowledgements: Thank you for Universitas Airlangga for supporting the research.