Comparison of Results between Topical Estrogen Treatment for Postmenopausal Vaginal Atrophy and Platelet-Rich Plasma Treatment

doi:10.21203/rs.3.rs-4360464/v1

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Comparison of Results between Topical Estrogen Treatment for Postmenopausal Vaginal Atrophy and Platelet-Rich Plasma Treatment

https://doi.org/10.21203/rs.3.rs-4360464/v1

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Introduction:

With the increasing life expectancy, postmenopausal vulvovaginal atrophy has become more prominent in current medical practice, given its impact on quality of life, sexual function, and pelvic floor health. PRP is considered safe and is a low-cost, simple, natural, and minimally invasive method for vaginal rejuvenation. We aim to compare the effects of hormonal treatment options and PRP application for postmenopausal vulvovaginal atrophy.

Materials and Methods

From a total of 66 patients, topical estrogen treatment was administered to 36 patients, while PRP treatment was performed for 30 patients who had previously received topical estrogen treatment without obtaining a response. To assess the impact of vulvovaginal atrophy and associated symptoms on the quality of life of patients, three different questionnaires, namely vaginal health index, female sexual function index, and vulvovaginal symptoms questionnaire, along with the visual analog scale, were administered at 4 weeks interval.

Results

In the assessment at the 12th week, the results obtained from the use of female sexual function index and vulvovaginal symptoms questionnaire in patients treated with PRP showed a significant difference compared to the results obtained from patients treated with topical estrogen (p: 0.004, p: 0.000).

Conclusion

Autologous platelet-rich plasma injection is a safe and effective minimal invasive monotherapy for postmenopausal VVA and, consequently, vulvovaginal rejuvenation. PRP injection has been regarded as a promising method for the treatment of VVA in postmenopausal patients with contraindications to hormone therapy and to improve hydration of the vaginal mucosa.

Platelet Rich Plasma

Topical Estrogen

Atrophic Vaginitis

Menopause is known to be a gradual and physiological event associated with ovarian insufficiency, leading to significant effects on the lower genital tract due to hypoestrogenism. In European countries, the average age of menopause is approximately between 46 and 50 years (1). With the increasing life expectancy, postmenopausal vulvovaginal atrophy (VVA) has become more prominent in current medical practice, given its impact on quality of life, sexual function, and pelvic floor health (2, 3). Under hypoestrogenic conditions, the vaginal epithelium undergoes thinning, the barrier function is lost, vaginal folds decrease, tissue elasticity diminishes, and the secretion activity of Bartholin glands decreases. This results in vaginal mucosal traumatization and painful sensations (4). Symptoms accompanying vaginal dryness due to hypoestrogenism may include itching, burning, discharge, and dyspareunia. The frequency of VVA, the severity of pathological changes, and the clinical course of the disease are dependent on the lenght of postmenopausal period.(5)

The main therapeutic goal in postmenopausal vaginal atrophy is the alleviation of symptoms. Low-dose vaginal Estrogen Therapy (ET) is the most widely used pharmacological treatment for VVA and is also the most effective and safe option. They facilitate the renewal of the epithelium and vaginal flora, leading to the improvement of urogenital and sexual complaints (5). During the use of low-dose vaginal ET, systemic estrogen absorption is minimal, and serum estradiol levels remain at postmenopausal levels (6–8).

In recent years, opinions and data on the use of Platelet-Rich Plasma (PRP) application in the treatment of postmenopausal vaginal atrophy have come into focus, becoming an actively discussed topic. PRP is considered safe and is a low-cost, simple, natural, and minimally invasive method for vaginal rejuvenation. Autologous growth factors which are the essentials for PRP include molecules such as Vascular Endothelial Growth Factor, Epidermal Growth Factor, and Platelet-Derived Growth Factor (PDGF), which stimulate cell proliferation and cell differentiation. These molecules play a crucial role in reducing inflammation, stimulating collagen III synthesis, promoting angiogenesis, and ultimately contributing to tissue regeneration. PDGF has been reported to stimulate cell proliferation and participate in wound healing (9, 10). Studies on PRP application in vulvovaginal atrophy are limited in the literature (11, 12).

Our study aims to compare the effects of ET and PRP application for postmenopausal vulvovaginal atrophy.

A total of 66 patients diagnosed with postmenopausal atrophic vaginitis who presented to our gynecology clinic between January 2019 and February 2022 were included in our study. The patients were divided into two groups based on the use of topical estrogen and PRP. Topical ET was administered to 36 patients, while PRP treatment was performed for 30 patients who had previously received topical ET without obtaining a response. Patients receiving ET were given a vaginal cream containing 0.625 mg per dose Conjugated Estrogen for 14 nights, followed by applying one dose every other night for the following 10 weeks.

Initially, venous blood samples were centrifuged at 2000 rpm for 10 minutes. The collected plasma was then subjected to centrifugation again in a plain tube at the same parameters. Platelet pellets and plasma samples were subsequently combined in a third tube. A 4 ml PRP treatment was administered using 30-G needles, with 1 ml injected separately into each of the four vaginal walls. This procedure was preceded by the application of topical anesthetic cream. Sessions were repeated every 4 weeks for a total of 3 sessions.

To assess the impact of VVA and associated symptoms on the quality of life of patients, three different questionnaires, namely Vaginal Health Index (VHI), Female Sexual Function Index (FSFI), and Vulvovaginal Symptoms Questionnaire (VSQ), along with the Visual Analog Scale (VAS), were administered at weeks 0, 4, 8, and 12. The VHI utilized a scale from 1 to 5 to analyze five components, namely elasticity, fluid volume, pH, epithelial integrity, and moisture. The minimum total score of 5 points indicates severe VVA, while the maximum total score of 25 points indicates the absence of clinical symptoms of VVA. The VAS scale ranges from 0 (complete absence of symptoms) at the left end to 10 (worst possible symptom) at the right end. Participants rated VVA symptoms (dyspareunia, dryness, or burning) on a scale from 0 to 10. The FSFI questionnaire, assessing six different domains—desire, arousal, lubrication, orgasm, satisfaction, and pain/discomfort—used a scale from 0 (no sexual activity in the last 4 weeks) or 1 (very dissatisfied) to 5 (very satisfied) at weeks 0, 4, 8, and 12. Throughout the study, a full-scale score ranging from 2.0 (severe dysfunction) to 36.0 (no dysfunction) was employed to evaluate sexual function, considering increased FSFI scores associated with symptom improvement. An optimal cutoff score of 26, reported by Wiegel and colleagues, is used to distinguish women with and without current sexual dysfunction. The VSQ consists of 21 questions, utilizing a scoring scale ranging from 0 to 21 for evaluation (13).

The study included postmenopausal women aged between 45 and 70 years, diagnosed with VVA, not currently on any systemic estrogen therapy for any reason. Women with a history of breast or endometrial cancer, abnormal uterine bleeding, acute thrombophlebitis, or previous thromboembolic disorders related to estrogen use in the past 6 months before the study, and those with any contraindications to estrogen therapy were excluded from the study.

The study was conducted in accordance with the principles of the Declaration of Helsinki, and ethical approval was obtained before the commencement of the research. The Levene test was employed to assess whether the study group exhibited equal variance and to test the homogeneity of variance. Skewness and kurtosis in the statistical data were found to be within the range of -1.5 to + 1.5, indicating that the data conformed to a normal distribution. Therefore, paired sample t-tests were conducted for dependent groups. As the age data did not exhibit a normal distribution, the Kruskal-Wallis analysis was performed to assess the significance of differences between group means. Statistical analysis of the research data was carried out using SPSS version 20 (IBM SPSS Statistics, IBM Corporation, Armonk, NY, USA). The results were evaluated at a significance level of p < 0.05 with a confidence interval of 95%.

The mean ages of the volunteers participating in the study, categorized into those using topical estrogen and those undergoing PRP treatment, were 57.17 ± 8.02 and 57.20 ± 7.75, respectively (range 45–70) (p = 0.986). When considering the initial assessment data for all the tests used in the evaluation, a difference was observed only in the VSQ test between the two groups. In terms of other assessments during the baseline period, the groups are similar. In the assessment at the 12th week, the results obtained from the use of FSFI and VSQ in patients treated with PRP showed a significant difference compared to the results obtained from patients treated with topical estrogen (p: 0.004, p: 0.000). This assessment is shown in Table 1.

Table 1

Comparison of baseline and endpoint data between groups.
	Topical Estrogen Group n: 36	PRP Group n: 30	Signficance (p)
Age	57.17 ± 8.02	57.20 ± 7.75	.986
VAS Scoring Innitial (Dyspareunia)	6.97 ± 1.23	6.67 ± 1.37	.344
VAS Scoring Innitial (Dryness)	6.17 ± 1.25	6.27 ± 1.08	.733
VAS Scoring Innitial (Burning)	6.11 ± 1.09	6.17 ± 0.87	.823
FSFI Scoring Innitial	22.47 ± 1.03	22.77 ± 0.94	.232
VHI Scoring Innitial	12.58 ± 3.38	12.80 ± 3.43	.798
VSQ Scoring Innitial	13.86 ± 1.13	15.07 ± 0.91	.000
VAS Scoring 12th week (Dyspareunia)	6.67 ± 0.89	6.27 ± 0.83	.066
VAS Scoring 12th week (Dryness)	5.97 ± 0.94	6.13 ± 0.82	.466
VAS Scoring 12th week (Burning)	5.75 ± 0.84	5.97 ± 0.61	.245
FSFI Scoring 12th week	23.50 ± 0.85	24.13 ± 0.86	.004
VHI Scoring 12th week	14.78 ± 2.43	15.67 ± 1.86	.107
VSQ Scoring 12th week	12.64 ± 0.76	13.70 ± 0.47	.000
Assestment made with one-way ANOVA test for groups comparison. Significant values are bolded.

In participants receiving topical estrogen, statistically significant differences were observed between measurements during 0–4 weeks, 0–8 weeks and 0–12 weeks for VAS for dyspareunia (p: 0.044, p: 0.044, p: 0.010); also a statistically significant difference was found between measurements during 0–8 weeks and 0–12 weeks for VAS for burning sensation. (p: 0.010, p: 0.002). No statistically significant difference was observed in measurements of VAS for dryness sensation within participants undergoing topical estrogen (p > 0.05).

For participants undergoing PRP, statistically significant differences were observed between measurements during 0–8 weeks and 0–12 weeks for VAS for dyspareunia. (p: 0.010, p: 0.005) No statistically significant difference was observed in measurements of VAS for dryness sensation within participants undergoing PRP (p > 0.05). A significant difference was found between measurements during 0–12 weeks for VAS for burning sensation in participants undergoing PRP (p: 0.031). The detailed results regarding other evaluation methods are presented in Table 2.

Table 2

Week to week analysis of differences compared to innitial results among two groups.
		Topical Estrogen Mean Difference n: 36	Significance (p)	PRP Mean Difference n: 30	Significance (p)
VHI Scoring	4th week	1.25 ± 0.65	.000	1.37 ± 0.72	.000
	8th week	2.08 ± 0.97	.000	2.37 ± 1.45	.000
	12th week	2.19 ± 1.28	.000	2.87 ± 1.98	.000
FSFI Scoring	4th week	0.78 ± 1.05	.000	0.77 ± 0.97	.000
	8th week	0.94 ± 1.09	.000	1.20 ± 1.10	.000
	12th week	1.03 ± 1.08	.000	1.37 ± 1.13	.000
VSQ Scoring	4th week	-0.78 ± 0.76	.000	-0.70 ± 0.75	.000
	8th week	-1.06 ± 0.95	.000	-1.20 ± 0.96	.000
	12th week	-1.22 ± 0.96	.000	-1.37 ± 1.07	.000
VAS Scoring (Dyspareunia)	4th week	-0.11 ± 0.32	.044	-0.20 ± 0.61	.083
	8th week	-0.22 ± 0.64	.044	-0.33 ± 0.66	.010
	12th week	-0.31 ± 0.67	.010	-0.40 ± 0.72	.005
VAS Scoring (Dryness)	4th week	-0.56 ± 0.33	.324	-0.10 ± 0.40	.184
	8th week	-0.19 ± 0.58	.051	-0.13 ± 0.43	.103
	12th week	-0.19 ± 0.58	.051	-0.13 ± 0.43	.103
VAS Scoring (Burning)	4th week	-0.08 ± 0.28	.083	-0.07 ± 0.25	.161
	8th week	-0.28 ± 0.62	.010	-0.17 ± 0.46	.057
	12th week	-0.36 ± 0.64	.002	-0.20 ± 0.48	.031
The assessment involved comparing the initial questionnaire scoring results for each successive week of the study, stratified by the administration of either topical estrogen or PRP. The analysis was done with paired samples test. Significant values are bolded.

In our study, we evaluated the mean differences in responses to questionnaires administered at 0, 4th, 8th, and 12th weeks following topical estrogen and PRP applications to monitor outcomes. Previously, in the REVIVE study, reported symptoms of vaginal atrophy in postmenopausal women included vaginal dryness (55%), dyspareunia (44%), vaginal irritation (37%), vaginal sensitivity (17%), bleeding during sexual intercourse (8%), and pain during exercise (2%) (14). In a separate study, vaginal dryness and dyspareunia emerged as the most prevalent symptoms, whereas itching, burning, vaginal discharge, a sensation of fullness, and coital bleeding may manifest as the condition progresses (15). In a study involving postmenopausal women aged 50–79, it is observed that 52% continue their sexual life, whereas in studies with women aged 70–79, this rate decreases to 22%.(16) Looking at the frequency of sexual symptoms experienced by postmenopausal women in the literature, Liu and Eden's 2007 study found it to be 41%, while Chen et al.'s 2007 study reported 49.3%.(17, 18) In our study, we employed a variety of questionnaires to address the different types of symptoms mentioned earlier in patients with VVA.

There was noted improvement in the VAS scores for dyspareunia between the 0-4th, 0-8th, and 0-12th weeks, as well as in the VAS scores for burning sensation between the 0-8th and 0-12th weeks, among the group using topical ET. In two similar studies the use of low-dose vaginal estrogen tablets was shown to be effective in reducing postmenopausal urogenital symptoms and reducing postmenopausal dyspareunia (19, 20). FSFI scores and VHI scores consistently demonstrated symptom alleviation across all weeks of measurement, similar to findings from two other studies that also employed FSFI and VHI. These studies both indicated significant improvement in the respective scores following a 12-week topical estrogen therapy (21, 22).

Two separate studies utilizing VHI, VSQ, and FSFI, significant improvement in scores was achieved in patients treated with PRP during their one month follow-up assessments (23, 24) In our study, participants who received PRP exhibited significant improvement in FSFI, VSQ, and VHI measurements throughout all weeks of the study, including the assessments conducted from week 0 to week 12. Hersant et al. observed improvement in clinical symptoms such as vaginal dryness and dyspareunia in all participants in their study.(25) In our study, participants who received PRP showed significant improvement in VAS for dyspareunia and VAS for burning sensation measurements from week 0 to week 12, while no significant improvement was observed in VAS for dryness sensation measurements. To date including our study, no adverse effects have been reported in the literature regarding vaginal PRP applications. This is explained by the fact that PRP content is obtained from the patient's own plasma.

To our knowledge, there are no other studies comparing the two methods for treating VVA. Therefore, when comparing the effectiveness of topical estrogen and PRP applications, it is noteworthy that although there was no significant difference in initial FSFI and VHI scores, a significant difference was observed in favor of PRP at the end of the 12th week.

We believe that our study contributes to the literature by comparing the efficacy of these two aforementioned applications. The strength of our study lies in the frequency of application and the duration of treatment, which surpasses that of other studies in the literature, many of which have shorter treatment durations. However, limitations of our study include a relatively small sample size and the lack of investigation into the partner's sexual dysfunction as a potential cause of female sexual dysfunction.

PRP application by injection is a safe and effective minimal invasive monotherapy for postmenopausal VVA. PRP injection has been regarded as a promising method for the treatment of VVA in postmenopausal patients with contraindications to hormone therapy and to improve hydration of the vaginal mucosa. The authors believe that larger randomized studies are necessary to comprehensively address the outcomes of primary PRP treatment for VVA.

Ethical approval: Ethical approval for this study was obtained from the ‘Buca Seyfi Demirsoy Training and Research Hospital’ on September 27, 2023, with the protocol number 2023/168.

Consent for publication: Not applicable

Consent to participate: All participiants were consented with informed consents approved by local ethical board.

Availability of data and materials: The datasets used and/or analyzed in relation to the current study are available from the corresponding author upon reasonable request.

Funding: The authors received no fnancial support for the research, authorship, and/or publication of this article.

Acknowledgements: Not applicable

Competing interests: The authors declare that they have no competing interests.

Authors’ information:

¹Private Karataş Hospital, Izmir, Turkey ²Demokrasi University, Buca Seyfi Demirsoy Training and Research Hospital, Department of Obstetrics and Gynecology, Izmir, Turkey

³ Dokuz Eylul University School of Medicine, Izmir, Turkey

All authors reviewed and approved the final version and no other person made a substantial contribution to the paper.

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No competing interests reported.

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Comparison of Results between Topical Estrogen Treatment for Postmenopausal Vaginal Atrophy and Platelet-Rich Plasma Treatment

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Materials and Methods

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Introduction

Materials and Methods

Results

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