Vaginal Laser Treatment for Genitourinary Syndrome of the Menopause: A Dose‐Determining Study in Breast Cancer Survivors

ABSTRACT

Objectives

Breast cancer survivors (BCSs) receiving endocrine therapy frequently develop genitourinary syndrome of menopause, characterized by vaginal dryness, pain, and urinary symptoms. Fractional CO₂ vaginal laser therapy has been proposed as a non‐hormonal management option, but the optimal number of treatment sessions remains unclear. As preparation for a forthcoming randomized, blinded, sham‐controlled trial, this dose‐determining study evaluated how the number of fractional CO₂ laser sessions influences urogenital symptoms and objective vaginal parameters to identify session‐dependent dose–response patterns.

Methods

This single‐center dose‐determining study was conducted at Randers Regional Hospital, Denmark. Thirty BCSs on endocrine therapy with symptomatic genitourinary syndrome of menopause underwent five monthly sessions of fractional microablative CO₂ vaginal laser using a standardized intravaginal probe protocol. Outcomes were evaluated at baseline and 4 weeks after the third, fourth, and fifth sessions. The primary outcome was vaginal dryness (VAS 0–10). Secondary outcomes included vaginal pain, itching, and soreness (VAS); sexual function (FSFI, SCS‐W); urinary symptoms (UDI‐6, ICIQ‐FLUTSsex); and vaginal health (VHI). Statistical analyses involved paired within‐participant comparisons across time points.

Results

Twenty‐seven participants (90%) completed all five sessions. Vaginal dryness decreased significantly after three treatments, with a further incremental reduction by the fifth, representing the largest session‐dependent change. FSFI scores increased significantly from baseline, with additional improvements across later sessions. SCS‐W and ICIQ‐FLUTSsex scores decreased steadily, while UDI‐6 improved from baseline but remained stable across subsequent assessments. Treatments were well tolerated, with no serious adverse events.

Conclusions

Fractional CO₂ vaginal laser therapy demonstrated incremental, session‐dependent changes in urogenital symptoms and vaginal health measures, with the greatest improvements after five sessions. The protocol was feasible and acceptable for BCSs receiving endocrine therapy. Overall, these findings provide clinically relevant dose–response insight to help guide optimization of treatment parameters ahead of future randomized, sham‐controlled trials overall.

Abbreviations

AIs

aromatase inhibitors

BCSs

breast cancer survivors

FSFI

Female Sexual Function Index

GSM

genitourinary syndrome of the menopause

ICIQ‐FLUTSsex

International Consultation on Incontinence Questionnaire—Female Lower Urinary Tract Symptoms sex

SCS‐W

Sexual Complaint Screener—Women

SERMs

selective estrogen receptor modulators

UDI‐6

Urogenital Distress Inventory

VAS

visual analog scale

VHI

Vaginal Health Index

1. Introduction

Breast cancer is the most prevalent cancer among women worldwide. Approximately 1 in 20 women are estimated to develop the disease during their lifetime, and over one‐third are diagnosed before the age of 55 [1]. Endocrine therapy is a cornerstone in reducing the risk of recurrence [2]. Endocrine therapy for breast cancer among pre‐ and perimenopausal women typically includes selective estrogen receptor modulators (SERMs) such as tamoxifen. For postmenopausal women, aromatase inhibitors (AIs), such as letrozole, are used to inhibit estrogen production [3]. With high and still increasing survival rates, the long‐term management of treatment‐related side effects has become an important aspect of survivorship care [4]. Both natural menopause and breast cancer treatment may substantially reduce estrogenic stimulation of the vulvovaginal and lower urinary tract tissues. This reduction may be particularly pronounced in women receiving aromatase inhibitors, which suppress peripheral estrogen production, and in premenopausal women undergoing ovarian suppression. Reduced estrogen exposure contributes to thinning of the vaginal epithelium, reduced lubrication and elasticity, increased vaginal pH, and urinary and sexual symptoms. As endocrine therapy is commonly prescribed for several years, these symptoms may persist and become more severe over time if left untreated, substantially impairing sexual health and quality of life. Alongside other treatment‐related adverse effects, severe genitourinary symptoms may also negatively affect adherence to endocrine therapy, thereby compromising the efficacy of the adjuvant treatment [5].

Genitourinary syndrome of the menopause (GSM) is highly prevalent among breast cancer survivors (BCSs), affecting up to 75% of women receiving endocrine therapy with symptoms such as vaginal dryness, dyspareunia, irritation, urinary incontinence, and impaired quality of life [5]. Standard hormone replacement therapies, while effective in postmenopausal women, have been shown to increase the risk of recurrence among estrogen receptor‐positive BCSs [6, 7]. Moreover, AIs may have reduced efficacy when combined with vaginal estrogen therapy [8]. Also importantly, many BCSs prefer to avoid any kind of estrogen‐based treatment [5]. Thus, there is a clear need for effective nonhormonal strategies to manage GSM in this population. Existing options—such as vaginal lubricants and moisturizers, dehydroepiandrosterone, ospemifene, and counseling—provide limited relief and are rarely sufficient as stand‐alone interventions [9].

Fractional CO₂ vaginal laser therapy has emerged as a potential non‐hormonal treatment for GSM, but most studies to date have focused on postmenopausal women without a history of cancer [10].

Evidence in BCSs remains limited, and key uncertainties persist regarding the optimal treatment regimen, including how many sessions are required to achieve meaningful improvement. Only one previous study has explored treatment repetition, reporting a linear symptom improvement across three to five sessions in naturally postmenopausal women [11]. However, this study was conducted in a non‐cancer population with different hormonal backgrounds, and it remains uncertain whether the same session pattern applies to endocrine‐treated BCSs.

The aim of this study was to examine whether three, four, or five sessions of fractional CO₂ vaginal laser therapy yield clinically relevant, session‐dependent improvements in GSM symptoms among BCSs receiving endocrine therapy.

2. Materials and Methods

2.1. Study Design and Setting

This single‐center study was carried out at the Department of Gynaecology and Obstetrics, Randers Regional Hospital, Denmark between February 2023 and April 2024. The study protocol was published in 2023 [12]. Trial approval was obtained from the Danish Data Protection Agency (1‐16‐02‐327‐22) and the Regional Science Ethical Committee (1‐10‐72‐183‐22), and the trial is registered at ClinicalTrials.gov (NCT06007027). This exploratory dose‐determining study evaluated cumulative session‐related changes after three, four, and five treatment sessions within the same participants. In this context, “dose” refers to the cumulative number of treatment sessions rather than different laser energy settings or separate treatment regimens.

2.2. Participants

Women were eligible if they had primary breast cancer, were receiving adjuvant endocrine therapy (SERMs or AIs), and were experiencing symptoms of GSM. Exclusion criteria were: age $\le$ 18 years; pelvic organ prolapse ≥ Stage II according to the Pelvic Organ Prolapse Quantification (POP‐Q) system; use of non‐hormonal vaginal therapies within 1 month before baseline; use of vaginal hormonal therapy within 12 months before baseline; chemotherapy treatment within 6 months prior to baseline; ongoing acute urinary tract infection; active genital infection; and a history of vaginal reconstructive surgery. All participants provided oral and written informed consent prior to the first laser treatment.

2.3. Intervention

Participants received five sessions of vaginal laser therapy using a fractional microablative CO₂ laser (SmartXideV²LR, MonaLisa Touch, DEKA, Florence, Italy) at 4–6‐week intervals. This interval was predefined in the study protocol [12] and reflected the approximately monthly schedule commonly used in previous clinical studies of fractional CO₂ vaginal laser therapy. Research Electronic Data Capture (REDCap), a secure web application for building and managing online surveys and databases, was used to administer the patient‐reported outcome questionnaires. The questionaries were distributed electronically 4 weeks after the third, fourth, and fifth treatment sessions and were completed by participants at home. Clinical assessments, including the Vaginal Health Index, were performed at the corresponding follow‐up visits. Treatments were administered in an outpatient setting without the use of topical anesthesia or vaginal gel. The laser settings were as follows: dot power 30 W, dwell time 1000 μs, dot spacing 1000 μm. SmartStack 2 was applied during the first three treatments and SmartStack 3 during the fourth and fifth. At the level of the vaginal introitus, dot power was reduced to 20 W in accordance with the predefined treatment protocol [12]. This lower setting was applied consistently to all participants, the introital tissue is more sensitive than the vaginal tissue, to improve treatment tolerability; it was not adjusted in response to individual discomfort.

2.4. Outcomes

The primary outcome was self‐reported vaginal dryness assessed on a 0–10 visual analog scale (VAS) in response to the question: “Have you experienced vaginal dryness during the past 14 days?.” VAS 0 = no bother, 10 = worst possible bother. Secondary VAS outcomes included vaginal pain, soreness, and itching (0–10). Additional secondary measures were sexual function, urinary symptoms, and vaginal health (VHI score). All patient‐reported outcomes reflected the preceding 14 days.

2.5. Sexual Function

Sexual function was assessed using the validated Female Sexual Function Index (FSFI), evaluating desire, arousal, lubrication, orgasm, satisfaction, and pain (score range 2–36; ≤ 26.55 indicates dysfunction) [13]. The FSFI reference period was adapted from 4 to 2 weeks to align with treatment intervals. The Sexual Complaints Screener for Women (SCS‐W), also a validated questionnaire, was administered (range 0–60), with higher scores indicating more severe sexual symptoms [14].

2.6. Urinary Symptoms

Symptoms were evaluated using the Urogenital Distress Inventory (UDI‐6), a validated tool for assessing irritative, obstructive, and stress urinary symptoms. Scores on the UDI‐6 range from 0 to 18, with higher scores indicating greater symptom burden [15]. Female sexual function in relation to lower urinary tract symptoms was assessed using the International Consultation on Incontinence Questionnaire for Female Urinary Tract Symptoms (ICIQ‐FLUTSsex), where scores range from 0 to 14, with higher scores reflecting increased symptom severity [16].

2.7. Vaginal Health Index

A gynecological examination was performed at baseline and after the third, fourth, and fifth treatments using the Vaginal Health Index (VHI). The VHI assesses moisture, fluid volume, epithelial integrity, elasticity, and vaginal pH (range 5–25, higher scores indicating better vaginal health).

2.8. Use of Artificial Intelligence Generated Content

An artificial intelligence–based language model (ChatGPT, OpenAI) was used to assist with language editing and linguistic refinement of the manuscript. The tool was applied solely to improve clarity, grammar, and readability of the text. No content, data analysis, interpretation of results, or scientific conclusions were generated by the AI tool. All final content was reviewed, edited, and approved by the authors, who take full responsibility for the manuscript.

2.9. Statistical Analyses

Data are presented as means $\pm$ standard deviations (SDs) or as frequencies (n) and percentages. The normality of data distribution was assessed visually via QQ plots and formally via the Shapiro–Wilk test. Depending on the distribution, comparisons across four time points (baseline, after the third, fourth, and fifth laser treatments) were made using the paired Student's t‐test or the Wilcoxon signed‐rank test. All statistical analyses were conducted using STATA, version 18.0. Data were stored in the Research Electronic Data Capture (REDCap) system [17, 18]. A one‐sided p value of 0.05 was considered statistically significant. The sample size and power calculation were detailed in the published study protocol [12].

3. Results

Thirty women were enrolled in the study. Three participants withdrew: one prior to the first treatment, and two after completing four sessions (one due to personal reasons unrelated to the study, and one due to transient vaginal soreness that resolved within 48 h). Baseline characteristics of the 27 participants who completed all five treatments are presented in Table 1.

Table 1.

Baseline characteristics of participants (N = 27).

Mean age (years)
At enrollment	54.4 (SD, 7.7; range, 40–72)
At menopause	47.6 (SD, 4.2; range, 38–57)
Mean BMI (kg/m2)	28 (SD;4.6)
Type of menopause, n (%)
Natural	15 (55.6)
Induced by the cancer treatment	12 (44.4)
Smoking status, n (%)
Current smokers	3 (11.1)
Former smokers	13 (48.1)
Never‐smokers	11 (40.7)
Parity, n (%)
Nullipara	4 (14.8)
Primipara	4 (14.8)
Multipara	19 (70.4)
Sexually active, n (%)	9 (33.3)
Mean time since breast cancer diagnosis (y)	3.4 (SD, 2.2; range, 1–10)
Nodal status, n (%)
No metastases (pN0)	17 (63)
Metastatic lymph nodes ($\mathit{\ge }$ pN1)	10 [37]
Surgery, n (%)	27 (100)
Chemotherapy, n (%)
Yes	18 (66.7)
No	9 (33.3)
Type of hormone therapy, n (%)
Selective estrogen receptor modulator (SERM)	9 (33.3)
Aromatase inhibitor (AI)	18 (66.7)

The mean age was 54.4 ± 7.7 years and mean body mass index 28.0 ± 4.6 kg/m². The average time since breast cancer diagnosis was 3.4 ± 2.2 years. Most participants (66.7%) were receiving adjuvant AI therapy, while the remaining 33.3% were treated with SERMs. Twelve women (44.4%) reported treatment‐induced menopause.

At baseline, nine participants (33%) answered “Yes” to the question: “Have you been sexually active within the past month?” (sexual activity defined as caressing, foreplay, masturbation, or vaginal intercourse). Among the 18 sexually inactive participants, 88% responded “Yes” to the question: “Would you like to have been sexually active?”

The mean number of laser shots per session was 31.5 ± 5.4 during the first treatment, 30.4 ± 4.2 during the second, 32.6 ± 6.7 during the third, 34.3 ± 6.7 during the fourth, and 35.7 ± 5.9 during the fifth. A mean increase of 3.2 ± 7.7 shots was observed between the third and fifth treatments (p = 0.05).

The primary outcome, vaginal dryness assessed on the VAS at four time points, is presented in Figure 1. A clinically significant reduction was observed from baseline (6.8 ± 2.6), with mean changes of −3.2 ± 3.0 after the third treatment, −3.1 ± 3.3 after the fourth, and −4.4 ± 3.2 after the fifth treatment (p < 0.01). No significant difference was observed between the third and fourth treatments. However,

Figure 1.

Vaginal dryness across four assessment time points. Vaginal dryness was assessed using a visual analog scale (VAS; 0 = no bother, 10 = worst possible bother). Blue boxes represent mean scores and red lines represent the 95% confidence intervals.

a further statistically significant mean reduction of 1.1 ± 3.3 was noted between the third and fifth treatments (p = 0.05).

Table 2 presents participants' evaluations of vaginal itch, soreness, and pain at baseline and after the third, fourth, and fifth laser treatments. Significant improvements in all symptoms were observed from baseline to each of the three follow‐up assessments. However, no additional significant differences were detected between the third, fourth, and fifth treatments.

Table 2.

Vaginal itch, soreness, and pain: mean scores and changes over time.

	Mean (SD)	Difference from baseline to after the third laser treatment, mean (SD) or median (IQR)	Difference from baseline to after the fourth laser treatment, mean (SD) or median (IQR)	Difference from baseline to after the fifth laser treatment, mean (SD) or median (IQR)	Difference from after the third laser treatment to after the fourth laser treatment, mean (SD) or median (IQR)	Difference from after third laser treatment to after the fifth laser treatment, mean (SD) or median (IQR)
Itch
At baseline After the third laser treatment After the fourth laser treatment After the fifth laser treatment	3.6 (3.1) 1.1 (1.9) 0.9 (2.1) 1.7 (2.4)	−1 (−5 to 0) p  < 0.01 a	−2.7 (3.7) p  < 0.01 b	−1.9 (3.0) p  < 0.01 b	0 (−1 to 0) p = 0.10a	0 (0–1) p = 0.19a
Soreness
At baseline After the third laser treatment After the fourth laser treatment After the fifth laser treatment	3.9 (2.7) 1.1 (1.2) 1.0 (1.7) 1.1 (2.1)	−2 (−5 to −1) p  < 0.01 a	−2.9 (2.9) p  < 0.01 b	−2.7 (3.4) p  < 0.01 b	0.1 (1.9) p = 0.42b	0 (−1 to 0) p = 0.36a
Pain
At baseline After the third laser treatment After the fourth laser treatment After the fifth laser treatment	6.3 (3.8) 3.4 (3.8) 3.4 (3.7) 2.8 (3.3)	−2.7 (5.4) p  = 0.02 b	−2.3 (4.6) p  = 0.04 b	−3.9 (6.2) p  < 0.01 b	−0.1 (4.3) p = 0.47b	−1.4 (3.7) p = 0.06b

Note: Vaginal itch, soreness, and pain were evaluated using a visual analog scale (VAS; 0 = no bother, 10 = worst possible bother). Statistical comparisons were performed between baseline and each follow‐up assessment, as well as between selected treatment sessions.

For comparisons analyzed using the paired Student's t‐test, changes are presented as mean differences with standard deviations (SD). For comparisons analyzed using the Wilcoxon signed‐rank test, changes are presented as median within‐participant differences with interquartile ranges (IQR). Corresponding p values are reported for all comparisons. Bold values indicate statistically significant differences (p < 0.05).

^a Differences tested with the Wilcoxon signed‐rank test.

^b Differences tested with the paired Student's t‐test.

Table 3 presents the mean scores and changes across the four assessment time points for the FSFI, SCS‐W, UDI‐6, and ICIQ‐FLUTSsex. The FSFI increased significantly from baseline to after the third, fourth, and fifth treatments (p < 0.05). A further significant increase of 3.4 ± 6.6 points was observed between the third and fifth treatments (p < 0.01), whereas no significant difference was detected between the third and fourth. Similar patterns were observed for the UDI‐6, with significant improvements from baseline but no additional differences between consecutive post‐treatment assessments. Scores on both the SCS‐W and ICIQ‐FLUTSsex decreased significantly from the third to the fifth treatment (p < 0.05), indicating a further reduction in symptom burden.

Table 3.

Female Sexual Function Index, Sexual complaint screener, Urogenital distress inventory, and ICIQ‐FLUTSsex: mean scores and changes over time.

	Mean (SD)	Difference from baseline to after the third laser treatment	Difference from baseline to after the fourth laser treatment	Difference from baseline to after the fifth laser treatment	Difference from after the third laser treatment to after the fourth laser treatment	Difference from after third laser treatment to after the fifth laser treatment
FSFI
At baseline After the third laser treatment After the fourth laser treatment After the fifth laser treatment	9.1 (6.6) 12.2 (9.2) 13.2 (9.7) 15.2 (10.3)	3.0 (7.6) p  = 0.04	3.7 (8.0) p  = 0.02	6.4 (8.8) p  < 0.01	0.5 (6.4) p = 0.37	3.4 (6.6) p  < 0.01
SCS women
At baseline After the third laser treatment After the fourth laser treatment After the fifth laser treatment	27.6 (10.9) 26.4 (9.8) 24.0 (11.5) 20.7 (7.8)	−1.0 (11.1) p = 0.34	−5 (16) p = 0.08	−7.6 (12.5) p = < 0.01	−3.2 (10.4) p = 0.10	−7.3 (8.5) p  = < 0.01
UDI‐6
At baseline After the third laser treatment After the fourth laser treatment After the fifth laser treatment	8.6 (4.7) 6.1 (4.4) 5.6 (3.6) 5.8 (4.0)	−2.4 (3.2) p  = < 0.01	−2.7 (3.4) p  < 0.01	−2.9 (3.8) p  < 0.01	−0.3 (3.0) p = 0.32	−0.5 (3.0) p = 0.20
ICIQ‐FLUTSsex
At baseline After the third laser treatment After the fourth laser treatment After the fifth laser treatment	11.1 (2.6) 9.6 (3.8) 8.1 (3.1) 7.9 (2.4)	−1.6 (3.6) p  = 0.03	−3.1 (3.0) p  < 0.01	−3.9 (3.2) p  < 0.01	−1.1 (3.1) p = 0.07	−2.5 (3.2) p  < 0.01

Note: The Female Sexual Function Index (FSFI) ranges from 2 to 36, with scores below 26.55 indicating sexual dysfunction. The Sexual Complaints Screener for Women (SCS‐W) ranges from 0 to 60, with higher scores indicating greater symptom severity. The Urogenital Distress Inventory (UDI‐6) ranges from 0 to 18, with higher scores reflecting greater symptom burden. The International Consultation on Incontinence Questionnaire–Female Urinary Tract Symptoms, sexual matters module (ICIQ‐FLUTSsex), ranges from 0 to 14, with higher scores indicating increased symptom severity. Differences between time points were tested using the paired Student's t‐test. Bold values indicate statistically significant differences (p < 0.05).

The VHI score improved significantly from baseline 12.0 ± 4.4 to 15.7 ± 5.3 after three treatments, 17.1 ± 5.0 after four treatments, and 17.3 ± 4.9 after five treatments (p < 0.01). Significant differences were also observed between the third and fourth treatments (p = 0.01) and between the third and fifth treatments (p < 0.01). Vaginal pH decreased significantly from 6.8 ± 1.5 at baseline to 6.4 ± 1.5, 6.3 ± 1.5, and 6.3 ± 1.6 after the third, fourth, and fifth treatments, respectively (p < 0.05), although this change was considered clinically negligible.

After five treatments, 22 participants (84.6%) reported reduced vaginal discomfort, and 21 participants (80.8%) answered “Yes” to the question: “Did vaginal laser treatment improve your overall daily life?” All 27 participants (100%) indicated that they would recommend vaginal laser treatment to a friend.

No serious adverse events occurred. Minor post‐treatment adverse effects included transient vaginal bleeding, discharge, itching, discomfort, and short‐term pain. Across the five treatment sessions, vaginal bleeding was reported by 34.5%–51.7% of participants with available data, vaginal discharge by 27.6%–44.8%, short‐term pain by 11.1%–27.6%, itching by 6.9%–13.8%, and general discomfort by 20.0%–27.6%. Session‐specific frequencies are presented in Table 4. One participant withdrew after the fourth treatment due to vaginal soreness, which resolved within 48 h.

Table 4.

Frequency of minor post‐treatment adverse effects after each laser treatment session.

Adverse event	After first, n/N (%)	After second, n/N (%)	After third, n/N (%)	After fourth, n/N (%)	After fifth, n/N (%)
Discomfort	6/28 (21.4)	6/29 (20.7)	6/28 (21.4)	8/29 (27.6)	5/25 (20.0)
Pain	4/29 (13.8)	8/29 (27.6)	5/29 (17.2)	5/29 (17.2)	3/27 (11.1)
Discharge	13/29 (44.8)	8/29 (27.6)	11/28 (39.3)	10/29 (34.5)	11/27 (40.7)
Itching	2/29 (6.9)	4/29 (13.8)	3/29 (10.3)	3/28 (10.7)	3/27 (11.1)
Bleeding	15/29 (51.7)	10/29 (34.5)	12/28 (42.9)	12/29 (41.4)	10/27 (37.0)

Note: Values are presented as n/N (%), where n is the number of participants reporting the minor adverse effect and N is the number of participants with available data for the respective minor adverse effect and treatment session. Adverse effects were self‐reported after each laser treatment session.

4. Discussion

In this exploratory dose‐determining study, clinically relevant improvements in vaginal dryness and several secondary outcomes were observed after three laser sessions, with smaller additional changes in selected outcomes after the fourth and fifth sessions. The largest observed reduction in vaginal dryness occurred after five sessions. However, because all participants received the same sequential five‐session regimen, these findings describe within‐participant changes over time rather than a direct comparison of separate treatment regimens. As CO₂ laser therapy may induce progressive tissue remodeling over several months, the present findings primarily reflect short‐term treatment effects, while the long‐term durability of these improvements warrants further investigation. Importantly, the five‐session regimen was generally well tolerated, with no unexpected or serious adverse events and only one withdrawal due to transient soreness. Participants reported subjective benefit and high acceptability, although these observations may reflect both specific and non‐specific effects of treatment in the context of an unblinded study design.

Our trial adds dose‐related information in a population underrepresented in previous laser research. Most previous studies have focused on otherwise healthy postmenopausal women or on heterogeneous cohorts combining BCSs, women with gynecologic malignancies, and women without cancer, often with variable endocrine backgrounds [19, 20, 21, 22, 23]. Only one prior study has explored the impact of increasing the number of CO₂ laser sessions on GSM. Athanasiou et al. reported progressive symptom improvements across three to five sessions in postmenopausal women without cancer [11]. However, as that study was conducted in naturally menopausal women, it remains uncertain whether similar patterns apply to endocrine‐treated BCSs, whose degree of estrogen deprivation be different from women in natural menopause, consequently the amount of mucosal atrophy and symptom burden may also differ from what is seen among women in natural menopause.

To our knowledge, this is the first dose‐determining study of vaginal laser treatment in BSCs. The evidence regarding the efficacy of CO₂ vaginal laser therapy in BCSs so far remains inconsistent. Most earlier studies included heterogeneous populations, potentially contributing to variability in outcomes. Our findings are broadly in line with two previous single‐arm studies using only three laser treatments in BCSs. Pearson et al. [24] and Quick et al. [25] both demonstrated improvements in vaginal dryness and sexual function using the FSFI, although without a comparator group these results must be interpreted cautiously.

Recent sham‐controlled trials in BCSs provide important context. Jaber et al. [26] found that both laser and sham groups improved after three treatments, with no significant between‐group differences. During the open‐label extension phase, women receiving active treatment showed further within‐group improvements. Similarly, Mension et al. [27] reported that both active and sham groups improved in FSFI and VHI scores following 5 monthly laser sessions, with no significant differences between groups at 6 months. The use of pre‐treatment lidocaine cream in some trials has been hypothesized to interfere with laser–tissue interaction, thereby compromising the effect of the laser treatment, though this remains unproven. In contrast, Salvatore et al. [28] observed symptom and VHI improvements after five sessions in a prospective cohort of BCSs, underscoring the heterogeneity of findings across study designs. Previous studies in BCSs have also reported variable laser settings or insufficient detail, limiting comparability and highlighting the need for standardized protocols. For example, Mension et al. [27] used higher power settings than those applied in our study, while Salvatore et al. [28] did not fully specify SmartStack use. Such inconsistencies further complicate cross‐trial interpretation.

The strengths of this study include the use of a standardized treatment protocol with repeated assessments after three, four, and five treatments; the use of validated symptom and function measures; and high participant compliance with minimal missing outcome data. Limitations include the small sample size, lack of blinding and sham control, short follow‐up, and inability to assess energy parameters beyond the settings used.

Vaginal dryness was the primary endpoint but not a required inclusion criterion, which may have introduced heterogeneity in baseline symptom severity. The study was not designed or powered to identify predictors of treatment response. Consequently, the small sample size precluded reliable assessment of whether symptom changes differed according to baseline symptom severity, menopausal status, type and duration of endocrine therapy, or time since breast cancer diagnosis. These factors may influence both GSM severity and treatment response and should be investigated in larger studies aimed at developing individually tailored treatment protocols.

Although the study was designed to explore session‐related dose patterns, all participants received the same sequential five‐session regimen. It therefore did not directly compare separate treatment regimens and cannot establish the minimum or optimal number of sessions. Rather, it identifies the earliest assessed time point at which improvements were observed and describes subsequent within‐participant changes. Furthermore, because assessments were performed 1 month after the third, fourth, and fifth sessions, the study provides information on short‐term session‐dependent changes rather than the durability of treatment effects. It cannot determine whether the additional changes observed after five sessions are further sustained than those observed after three sessions or whether maintenance treatments are required. Beyond treatment frequency, laser effects may also vary according to power, SmartStack settings, dot spacing, dwell time, and number of laser shots delivered, parameters that are inconsistently reported in existing literature. These uncertainties highlight the need for larger dose‐finding studies with longer follow‐up to develop standardized, evidence‐based treatment protocol for GSM, particularly among endocrine‐treated BCSs, and to inform adequately powered sham‐controlled trials.

5. Conclusion

Fractional CO₂ vaginal laser therapy was associated with clinically relevant within‐participant improvements in GSM symptoms among BCSs receiving endocrine therapy. Improvements were observed at the first assessment after three sessions, with smaller additional changes in selected outcomes after five sessions. Treatment was feasible, acceptable, and generally well tolerated. However, the small sample size, absence of a sham control, short duration of follow‐up, and lack of a direct comparison between different numbers of treatment sessions limit the strength of the conclusions. The findings should therefore be considered exploratory and hypothesis‐generating. Future randomized, blinded, sham‐controlled trials with longer follow‐up are needed to assess clinical efficacy, durability, and the optimal treatment regimen.

This work was supported by several foundations that provided salary, running costs, and equipment for Sine Jacobsen's 3‐year PhD fellowship. None of the funders had any role in study design, data collection, analysis, interpretation, or manuscript preparation. The CO₂ vaginal laser device was loaned by the manufacturer, which did not participate in recruitment, treatment, or data analysis. Participants received no compensation and incurred no expenses for their involvement.

• The Research Fund, Randers Regional Hospital, Denmark (no grant identifier)—1 year's salary.

• The Health Research Foundation of Central Denmark Region (no grant identifier)—1 year's salary.

• The Danish Cancer Society (Grant identifier: R325‐A18816)—1 year's salary, running costs, and equipment.

• The A.P. Moeller Foundation for the Advancement of Medical Science (Grant identifier: L‐2023‐00119)— running costs and equipment.

• The Danish Medical Association's Research Fund (Grant identifier: 2023‐0090)—running costs and equipment.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.