Er:YAG Laser Combined With Vaginal Estriol for Genitourinary Syndrome of Menopause

Effects of Erbium:YAG Laser Combined With Vaginal Estriol Therapy in Postmenopausal Women With Genitourinary Syndrome of Menopause: A Protocol for a Randomised, Double-blind Controlled Trial

Chronic hypoestrogenism in postmenopausal women significantly impacts the urogenital epithelium, leading to Genitourinary Syndrome of Menopause (GSM) and increasing susceptibility to gynecological infections due to vaginal pH elevation. Therapies using the Erbium:YAG (Er:YAG) 2940nm laser and low dose topical estrogen have demonstrated efficacy in improving vaginal trophism and restoring microbiota balance.

This randomised, double-blind clinical study aims to assess the effects of combining Er: YAG laser therapy with vaginal estriol compared with estriol therapy alone in postmenopausal women with GSM. Sixty patients will be recruited and randomly assigned to two groups. All participants will receive low-dose topical estrogen therapy (estriol cream ) for 14 days, followed by twice-weekly applications until completing three laser sessions at four-week intervals. Group 1 (Sham) will receive the laser with minimal fluence (0.5J/cm²) applied to maintain blinding (auditory cues) below the threshold for biological tissue, while Group 2 , will undergo active laser treatment.

Inclusion criteria include age 45-70 years, vaginal pH ≥5, absence of hormone therapy or energy-based intimate treatments for 180 days, and moderate vaginal atrophy symptoms (SCORE >4). Exclusion criteria include abnormal cervicalvaginal cytology in the last six months, corticosteroid therapy within 90 days, and BMI ≥35kg/m².

Assessments will occur at Baseline, 30 days after each laser session and 4 months after the third laser application. The primary outcome is the Vaginal Health Index (VHI), while secondary outcomes include GSM symptom evaluation via the Visual Analog Scale, vaginal microbiota analysis through 16S gene sequencing, and quality-of-life and sexual health questionnaires. Statistical analysis of the groups will be performed using SPSS version 22.0. For analytical statistics, repeated measures ANOVA will be used for continuous data, and non-parametric tests for repeated measures, such as the Friedman test, when appropriate. A p-value <0.05 will be considered statistically significant.

Study Overview

• Status: Recruiting
• Conditions: Genitourinary Syndrome of Menopause
• Intervention / Treatment: Drug: Topical estrogen therapy based on estriol (E3); Radiation: Sham Er:YAG laser (minimal fluence); Radiation: Active Er:YAG Laser

Detailed Description

Chronic, progressive hypoestrogenism, without adequate treatment during the postmenopausal period, significantly affects the epithelium of the urogenital system, causing Genitourinary Syndrome of Menopause (GSM). This disorder impacts the quality of life of thousands of women, favoring the emergence of other pathologies, including increasing the risk of gynecological infections from opportunistic microorganisms due to the elevation of vaginal pH, destabilizing the natural immunological barrier. Therapies using the Erbium:YAG (Er:YAG) 2940nm laser and low-dose topical estrogen therapy have demonstrated safety and efficacy in improving vaginal trophism, being crucial for the reestablishment of appropriate flora.

This study aims to assess the effects of combining Er: YAG laser therapy with vaginal estriol compared with estriol therapy alone in postmenopausal women with GSM. This is a randomised, double-blind clinical study. Sixty patients will be recruited and randomly divided into two groups. All participants will receive low-dose topical estrogen therapy (vaginal estriol cream (1 mg/g) administered intravaginally using disposable applicators pre-set to deliver 0.5 g per application (equivalent to 0.5 mg of estriol per dose) for 14 consecutive days and then twice weekly until completing three sessions of laser treatment, with a 4-week interval between sessions. In Group 1 (Sham), the laser will be applied with minimal fluence (0.5 J/cm²) to maintain blinding (auditory cues) below the threshold for biological tissue, while in Group 2, will be applied an active Er:YAG laser intervention. The intimate laser session consists of two stages: the internal stage ( vaginal canal) with energy settings of 9J/cm² at 2Hz and the external stage (vulvar and vestibule region) with energy settings of 6J/cm² at 2Hz.

Inclusion criteria include age between 45 and 70 years, vaginal pH level ≥5, absence of hormone therapy and intimate treatments using energy for 180 days, and presence of moderate symptoms of vaginal atrophy (SCORE >4). Exclusion criteria include altered cervical-vaginal cytology in the last six months, corticosteroid therapy within the last 90 days, and BMI ≥35kg/m².

The Vulvovaginal Health Index (VHI) is defined as the primary outcome of this study. Secondary outcomes will include the Visual Analog Scale for four symptoms of GSM (burning, irritation, dyspareunia, and persistent leukorrhea), vaginal microbiological sampling for DNA sequencing analysis using the 16S gene amplification technique, specifically at the V3/V4 region (before the first laser therapy session and 4 weeks after the third application), quality of life, and sexual health questionnaires.

Comparisons between the two groups will be conducted at Baseline, 30 days after each laser session and 4 months after the third laser application. Although data will be collected at multiple time points using validated instruments and laboratory assessments, the primary analysis will focus on predefined time points. Specifically, comparisons will be conducted between baseline and two post-intervention time points: (1) at the third laser session and (2) at follow-up, defined as four months after the third laser session.

Data will be collected using coded identifiers and stored on a secure, password-protected institutional server with restricted access. Regular data back-ups will be performed. Access to identifiable data will be limited to authorised members of the research team. De-identified data will be made available upon reasonable request, subject to appropriate ethical approval and the completion of a data sharing agreement. Further details are available via the study repository on the Open Science Framework (OSF): https://osf.io/dwgvx/.

Statistical analysis of the groups will be performed using SPSS version 22.0. For analytical statistics, repeated measures ANOVA will be used for continuous data, and non-parametric tests for repeated measures, such as the Friedman test, when appropriate. A p-value <0.05 will be considered statistically significant.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stella Zamuner; Phone Number: +55 11 3385-9241; Email: stella.rz@uni9.pro.br

Study Locations

• Brazil
  • São Paulo
    • São Paulo, São Paulo, Brazil, 01525-000
      • Recruiting
      • Universidade Nove de Julho
      • Contact: Stella Regina Zamuner, pHD, MD; Phone Number: +551133859241; Email: stella.rz@uni9.pro.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria

• Postmenopausal women (45-70 years of age).
• At least one of moderate symptom of GSM (vaginal dryness, burning sensation, dyspareunia, and persistent leukorrhea), defined by ≥ 4 on Visual Analog Scale (VAS) ranging from 0 to 10.
• Vaginal pH ≥5.0 at baseline assessment.
• Not having undergone hormone replacement therapy (vaginal or systemic) in the previous six months.
• No use of vaginal moisturizers in the previous 30 days.
• Demonstrated capacity and willingness to provide written informed consent and adhere to study protocols.

Exclusion criteria

• Vaginal or vulvar energy-based interventions (e.g., laser, radiofrequency) in the previous six months.
• Abnormal cervical cytology, specifically ASCUS, LSIL, or HSIL, documented in the previous six months.
• Systemic corticosteroid therapy administered in the previous 90 days.
• Body mass index (BMI) ≥35 kg/m².
• Presence of abnormal uterine bleeding in the previous 30 days.
• History of vaginal surgery in the previous 180 days or grade II or higher uterine prolapse (POP-q).
• History of malignant neoplasms or exposure to vaginal radiotherapy.
• Diagnosis of severe liver or kidney disease, autoimmune disease, or severe psychiatric disorder.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GROUP 2 ( Vaginal estriol plus active Er:YAG laser); All participants will receive vaginal estriol therapy combined with an active Er:YAG (λ = 2940 nm) . Participants will undergo three laser applications at four-week intervals. The intimate laser session consists of two stages using a PS03 fractional tip: the internal stage (vaginal canal) with energy settings of 9 J/cm² at 2 Hz, and the external stage (vulvar and vestibule region with energy settings of 6 J/cm² at 2 Hz.The laser device to be used is the Smooth XS Dynamics Dualis (FOTONA, Ljubljana, Slovenia) with a wavelength of 2940 nm.	Drug: Topical estrogen therapy based on estriol (E3); All participants will use low-dose Vaginal estriol cream (1 mg/g) administered intravaginally using disposable, individualized vaginal applicators pre-set at the recommended dosage of 0.5g/ per application (equivalent to 0.5 mg of estriol per dose). Induction phase: 0.5 g once daily at bedtime for 14 consecutive days. Maintenance phase: 0.5 g twice weekly for 16 weeks, on Mondays and Thursdays. The treatment will be provided in fractions for each 30 day period and will always be delivered after each laser session, along with a leaflet containing usage, storage, and application instructions for the vaginal cream. The patients will be monitored through a messaging app, reinforcing the instructions and the days of application correctly.; Other Names: Estriol ( E3); Vaginal estriol ( E3); Radiation: Active Er:YAG Laser; All participants in the group will undergo 3 applications of active Er:YAG laser with an interval of 4-5 weeks between them. The intimate laser session consists of two stages using a PS03 fractional tip: the internal stage (vaginal canal) with energy settings of 9 J/cm² at 2 Hz, and the external stage (vulvar and vestibule region) with energy settings of 6 J/cm² at 2 Hz.The laser device to be used is the Smooth XS Dynamics Dualis (FOTONA, Ljubljana, Slovenia) with a wavelength of 2940 nm.; Other Names: Laser On; Laser in Active Intervention Mode
Sham Comparator: GROUP 1 (Vaginal estriol plus Sham Er:YAG laser (minimal fluence)); All participants will receive vaginal estriol therapy combined with Er:YAG laser intervention with minimal fluence (0.5 J/cm²), below the therapeutic range reported for GSM, and not expected to induce clinically meaningful tissue effects, applied to maintain participant blinding through auditory and procedural cue. Participants will undergo three laser applications at four-week intervals. The intimate laser session consists of two stages using a PS03 fractional tip: the internal stage (vaginal canal) with energy settings of 0.5 J/cm² at 2 Hz, and the external stage (vulvar and vestibule region) with energy settings of 0.5J/cm² at 2 Hz.	Drug: Topical estrogen therapy based on estriol (E3); All participants will use low-dose Vaginal estriol cream (1 mg/g) administered intravaginally using disposable, individualized vaginal applicators pre-set at the recommended dosage of 0.5g/ per application (equivalent to 0.5 mg of estriol per dose). Induction phase: 0.5 g once daily at bedtime for 14 consecutive days. Maintenance phase: 0.5 g twice weekly for 16 weeks, on Mondays and Thursdays. The treatment will be provided in fractions for each 30 day period and will always be delivered after each laser session, along with a leaflet containing usage, storage, and application instructions for the vaginal cream. The patients will be monitored through a messaging app, reinforcing the instructions and the days of application correctly.; Other Names: Estriol ( E3); Vaginal estriol ( E3); Radiation: Sham Er:YAG laser (minimal fluence); All participants in the group will undergo 3 sham applications of Sham Er:YAG laser intervention delivered at minimal fluence (0.5 J), below the threshold for biological tissue effect, applied to preserve participant blinding through auditory and procedural cues , with an interval of 4-5 weeks between them. The intimate laser session consists of two stages using a PS03 fractional tip: the internal stage (vaginal canal) with energy settings of 0.5 J/cm² at 2 Hz, and the external stage (vestibule and introitus region) with energy settings of 0.5 J/cm² at 2 Hz.The laser device to be used is the Smooth XS Dynamics Dualis (FOTONA, Ljubljana, Slovenia) with a wavelength of 2940 nm.; Other Names: Laser in Minimal Fluence

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of the Vaginal Health Index (VHI)	Clinically assesses the degree of genital atrophy through physical examination, which analyzes "urogenital health." This is useful for the longitudinal follow-up of patients, where changes occurring in the genitourinary tract are noted, including the analysis of the need for therapeutic intervention. The parameters analyzed are: total elasticity, type and consistency of fluid secretion, Vaginal pH, epithelial mucosa, and moisture, which, according to their characteristics, receive scores from 1 to 5. The lower the score, the greater the degree of urogenital atrophy. Vaginal pH will be assessed as an integral component of the Vaginal Health Index and will not be analysed as a separate outcome measure.	Baseline, 30 days after each laser session and 4 months after the third laser application.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vaginal Microbiome	The analytical methodology involves sequencing the 16S rRNA gene (V3/V4) after DNA extraction using the "ZymoBIOMICS DNA Miniprep" kit, following the manufacturer's guidelines provided by "Biomehub Research and Development S.A." For bacterial identification, library preparation will be performed through amplification of the V3/V4 regions (341F and 806R) using a two-step PCR. The first PCR employs universal oligonucleotides for the V3/V4 region, while the second incorporates sequencing indexes. Sample collection will be conducted individually by the responsible researcher before the first laser session and four weeks after the third application. Statistical evaluations will include descriptive analysis, alpha diversity, beta diversity, and differential abundance between groups. Samples will be stored for three months and subsequently discarded by the contracted laboratory, adhering to the manufacturer's recommendations.	Before first laser session and four weeks after the third laser application.
Visual Analog Scale (VAS)	Four types of symptoms of GSM (dryness, burning, dyspareunia, and chronic leukorrhea) will be evaluated separately by the patient according to the VAS criteria, ranging from 0 (absence of symptoms) to 10 (very severe symptoms). Moderate symptoms will be considered with values equal to or greater than 4.	baseline, 30 days after each laser session and four months after the third laser application
Quality of Life Evaluation Questionnaires: Menopause Rating Scale (MRS)	Used to assess quality of life and symptoms related to climacteric. It consists of 11 questions distributed to analyze three parameters: somato-vegetative symptoms, psychological symptoms, and urogenital symptoms, which are classified into five degrees: none, mild, moderate, severe, and extremely severe. The higher the score, the greater the severity of the symptoms and, consequently, the worse the quality of life for the woman during the climacteric.	Baseline, 30 days after each laser session and 4 months after the third laser application.
Female Sexual Function Index (FSFI)	A tool used to evaluate female sexual response, based on the analysis of six domains: sexual desire, sexual arousal, vaginal lubrication, orgasm, sexual satisfaction, and pain. This assists in understanding how various factors, including health, relationships, and psychosocial factors, influence sexual satisfaction.	Baseline, 30 days after each laser session and 4 months after the third laser application.

Collaborators and Investigators

• Sponsor: University of Nove de Julho

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2025
• Primary Completion (Estimated): November 10, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 21, 2025
• First Submitted That Met QC Criteria: March 11, 2025
• First Posted (Actual): March 13, 2025

Study Record Updates

• Last Update Posted (Actual): April 23, 2026
• Last Update Submitted That Met QC Criteria: April 20, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: postmenopausal women; vaginal microbiome; Genitourinary syndrome of menopause; Erbium: YAG laser; vaginal estriol
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Syndrome; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Equipment and Supplies; Optical Devices; Radiation Equipment and Supplies; Steroids; Fused-Ring Compounds; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Lasers; Estriol
• Other Study ID Numbers: ERBIUM-YAG-LASER

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) that underlie the results reported in this study, after de-identification, will be shared upon reasonable request. Supporting documents, including the study protocol, statistical analysis plan, and analytic code, will also be made available.
• IPD Sharing Time Frame: Data will be available immediately following publication and will remain accessible for five years thereafter.
• IPD Sharing Access Criteria: Data will be shared with researchers who provide a methodologically sound proposal for its use, subject to approval by the study investigators. Access may require the signing of a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No