Supplemental Digital Content 3

(1)

CO₂ Clinical Studies Device

Name

Type of Study Methods Results Adverse Side

Effects SmartXide²

V²LR;

Monalisa Touch, DEKA, (Florence, Italy)

Retrospective Cohort

N=94⁷² Level 3

94 patients with symptoms of GSM underwent

treatment every 30 days.

35, 35, and 24 women received three, four, and five therapies, respectively.

Follow-ups occurred at 1, 3, 6, and 12 months after the last laser therapy. The VAS, ICIQ-UI SF, ICIQ- FLUTS, UDI-6, and FSFI were used to evaluate results.

GSM symptom improvements were

statistically significant. The intensity of dyspareunia and dryness decreased from 9 (5-10) (median [minimum-maximum]) and 8 (0-10) at baseline to 0 (0-6) and 0 (0-8), 1 month after last laser therapy (all P < 0.001), respectively.

The FSFI and frequency of sexual intercourse

increased from 10.8 (2- 26.9) and 1 (0-8) at baseline to 27.8 (15.2- 35.4) and 4 (2-8) 1 month after last laser therapy (all P < 0.001), respectively.

These positive effects remained unchanged

No

(2)

throughout the 12 months of follow-up.

CO2RE Intima, Syneron Candela, (Wayland, MA)

Prospective, Investigational N=40⁷³ Level 4

40 postmenopausal women underwent 3 monthly treatments. Results were evaluated using the VHI, ICIQ-UI, FSFI, a 10-point numerical scale for severity of vaginal dryness, burning, dyspareunia, and dysuria, and a 5-point Likert scale for satisfaction. Follow-up evaluations were at one, 3, 6, and 12 months after the third treatment. Biopsies were taken before the first treatment and at the 3 and 6 month follow-ups by one investigator for a few patients with visibly atrophied vaginal tissue.

The VHI scores improved significantly after the first treatment and were maintained with mean improvement of 9.6 ± 3.3 (P < 0.001) and 9.5 ± 3.3 (P < 0.001) at the 6 and 12-month follow-ups, respectively. Vaginal symptoms of dryness, itching, and dyspareunia improved significantly (P <

0.05) at all evaluations.

Histological findings showed increased collagen and elastin, as well as a thicker epithelium with an increased number of cell layers and a better degree of surface

maturation.

2 cases of mild itching and

discomfort, 1 case of mild swelling, 2 cases of

moderating burning with urination, 1 case of moderate soreness and spotting, 1 case of major itching, and 1 case of a possible yeast infection. These were reported within a 1 week follow-up period.

SmartXide² V²LR;

Prospective Cohort

184 patients received 3 laser applications at an

95.4% of the patients declared that they were

Not specified

(3)

N=184⁷⁴ Level 2

interval 4 weeks between sessions: baseline (T1), 30 days (T2) and 60 days (T3). Women were divided into groups with 128 classified as having spontaneous menopause and 56 having oncological menopause. Patients’

satisfaction was measured on 5-point Likert scale at 4 weeks and 6, 12, 18, 24 months.

satisfied or very satisfied with the procedure at 4 weeks after treatment. At 6 months 92% of patients were satisfied; at

12 months 72% were satisfied; at 18 months 63% were satisfied; at 24 months 25% of patients answered they were still satisfied. 4.6%, who were very dissatisfied with the treatment at T4, were all affected by chronic conditions involving epithelium in autoimmune damage. The comparison between the 2 groups revealed that the time interval from onset of menopause is a statistically significant factor in treatment satisfaction. Oncologic patients are proven to

(4)

undergo treatment at a younger age than other women (mean age 53 versus 57) but they usually do it after a shorter amount of time from their last period than women who had spontaneous menopause (6 years versus 9 years). The time period spent in absence of estrogenic stimulation can affect the tissue response to laser therapy.

SmartXide², MonaLisa Touch, (Florence, Italy)

Pilot N=30⁷⁵ Level 4

30 women with GSM and VVA underwent 3

treatments at an interval of 6 weeks. Outcomes were assessed using the VAS, VHI, FSFI, SF-12, a 5-point Likert scale, and the PGI-I.

Follow-ups occurred at 3 months after the final treatment.

The average improvement in VAS scoring was 1.7 ± 3.2 for pain, 1.4 ± 2.9 for burning, 1.4 ± 1.9 for itching, 6.1 ± 2.7 for dryness, 5.1 ± 3.0 for dyspareunia, and 1.0 ± 2.4 for dysuria; improvement in average VHI and FSFI scores were statistically significant (P < 0.001).

2 women reported mild-to-moderate pain lasting 2 to 3 days and 2 reported minor bleeding lasting less than 1 day.

None were discontinued due to the occurrence of adverse events.

(5)

Before the second and third treatments, 86.6% of women reported they were better or much better than at the previous treatment;

96% were reportedly satisfied or extremely satisfied at follow-up.

SmartXide² V²LR;

Prospective N=55⁷⁶ Level 4

55 postmenopausal women with moderate to severe symptoms of dyspareunia, were treated with 3

sessions. 53 women received an extra fourth session and 22 received an extra fifth session

depending on their

preference and evaluation of symptoms. The VAS, FSFI, VHIS, and VMV were used to evaluate results.

Following the third, fourth, and fifth sessions

respectively: dyspareunia completely regressed in 27%, 58%, and 81% of women, dryness

completely regressed in 36%, 66%, and 86%, normal sexual function resumed in 41%, 69%, and 84%, VMV regained non- atrophic values in 53%, 69%, and 84%, and VHIS regained non-atrophic values in 80%, 96%, and 100% of women. The total FSFI score, dyspareunia

Some participants reported a mild irritation at the introitus during the procedure and/or immediately after that resolved spontaneously.

(6)

and dryness symptoms were statistically significantly better for participants who received 4 sessions compared to 5.

AcuPulse System, FemTouch Handpiece, Lumenis, (Yokneam Industrial Park, Israel)

Prospective N=28⁷⁷ Level 4

28 postmenopausal women with VVA related symptoms underwent 3 treatments, in 4-week intervals. VHIS scores and VVA symptom severity were recorded at each visit. Sexual function was assessed with the FSFI. Follow-ups occurred at 3 and 6 months.

1 month following the first laser treatment, the mean VHIS score was

significantly improved (13.89 ± 4.25 vs. baseline 11.93 ± 3.82; p < 0.05) and improved further at 3 and 6 months following all three laser treatments (16.43 ± 4.20 and 17.46 ± 4.07, respectively). Almost all VVA symptoms were significantly improved at 1 month following the first treatment. A further significant improvement in VVA symptoms was noted at 3 and 6 months

following the third laser treatment. The FSFI score

Adverse events reported during the study were of moderate severity and were unrelated to the procedure. 1 case of vaginal bleeding was reported 1 month after the last treatment.

No subjects were discontinued due to an adverse event.

(7)

increased significantly (22.36 ± 10.40 vs. baseline 13.78 ± 7.70; p < 0.05) and remained significantly higher than baseline at the 3 and 6-month follow-up visits.

Retrospective Chart Review N=31⁷⁸

Level 4

A retrospective chart review of postmenopausal women and women with a history of breast cancer, symptoms of GSM and who were treated with endocrine therapy and received laser treatment was performed. The FSFI, WBFS, and FSDSr were used to evaluate results at baseline and 6 weeks after each treatment.

There was a statistically significant improvement in every domain of the FSFI, WBFS, and FSDS-R when comparing baseline

symptom scores to after treatment 3 symptom scores for all patients. The secondary outcome was to evaluate the differences in outcomes of sexual function between

postmenopausal women and women with a history of breast cancer treated with endocrine therapy.

Both groups had statistically significant

Not specified

(8)

improvements in vaginal itching, burning, dryness, painful intercourse, and overall sexual distress.

Prospective Cohort N=45⁷⁹ Level 2

45 women with signs and symptoms of urogenital atrophy underwent 5

treatments at 0, 1, 2, 3, and 6 months. 13 patients had a history of breast or endometrial cancer.

Patients were evaluated for reduction of signs and symptoms with the VHI, VAS, SF-12, FSFI and a 5- point Likert scale for satisfaction. Patients were evaluated every visit and 3 and 6 month follow-ups occurred after the last session of laser therapy.

38 patients completed the 6 month follow-up after the fifth laser session. 90% of patients with dryness who completed follow-up reported reduction of dryness, and 89.5% of the 19 patients with

dyspareunia who completed follow-up reported reduction of dyspareunia. 68.4% of patients reported satisfaction with the treatment at 6 months, 60.5% saw improvements in their VHI score which was found statistically significant at (p<0.05).

63.6% of patients who had a history of breast or

Discomfort during probe insertion and vaginal soreness for 1-2 days after the procedure.

(9)

endometrial cancer saw an improvement of their VHI score at 6 months. The VAS, FSFI, and SF-12 were not used for all patients due to difficulty in understanding.

FemiLift, Alma Lasers (Buffalo Grove, IL)

Prospective Comparative N=33⁸⁰

Level 2

33 postmenopausal patients with vaginal atrophy and/or SUI, underwent 3 vaginal treatment sessions, performed at 1-month intervals. 15 subjects had a history of cancer.

Symptoms were evaluated before treatment and at every subsequent

treatment session, as well as 3 months following the last treatment session. The VAS, ICIQ-UI, and VHIS were used at the first treatment and 3 month

There was significant improvement in dryness, burning, dyspareunia and VHIS scores (P < 0.01).

Reductions in the

frequency and severity of SUI symptoms (P < 0.01) was noted during the treatment period and maintained for at least 3 months after completion of the treatments. 90% of patients were satisfied with the procedure and

reported a significant improvement in quality of life. Histology samples post treatment revealed

No

(10)

follow-up. Biopsies were taken at the follow-up.

restoration of the epithelial and subepithelial

structures, characteristic of reproductive age vaginal mucosa.

SmartXide² V²LR;

Prospective Comparative N=87⁸¹ Level 2

87 women with symptoms of VVA underwent 3 monthly laser treatments.

13 patients had previous breast cancer. Time points of the study were at the screening visit (T0), at baseline (T1), at week 4 (T2), at week 8 (T3), after 3 months since the last laser application (T4), after 6 months (T5), after 9 months (T6), after 12 months (T7) and after 15 months (T8). Results were evaluated using the VAS, DIVA, VHI, and VVHI.

Before treatment, 35% of patients were sexually inactive due to VVA, and after 2 laser sessions, 13%

remained inactive. Among sexually active women, the mean VAS score for dyspareunia indicated severe symptoms at T1 and was considered

moderate at T3 with further improvement at T4 (mild symptoms, p<0.001).

Vaginal dryness improved from severe at baseline to moderate after 1

treatment. Vaginal dryness was considered mild at T4 and remained mild though the follow-up period.

Not specified

(11)

(p<0.001). The VHI score improved from T1, in which all women reported

atrophy, to T7, where 88%

of women reported no more vaginal atrophy (p<0.001). The VVHI improved from T1, in which all women reported VA, to T7, in which VA was reported by less than 5%

of subjects (p<0.001).

Quality of life measured by the DIVA improved at T4 in comparison to T1. The sexual functioning section on the DIVA questionnaire improved from 1.7+-3.1 at T1 to 4.8+-4.6 at T4. At T4, 37.7% of women were very satisfied, 52.9% were satisfied, 7.1% were uncertain, and 2.4% were very dissatisfied.

(12)

Women with previous breast cancer (coefficient - 1.81:p=0.022) showed a higher probability to report vaginal atrophy.

SmartXide² V²LR;

Prospective N=20⁸² Level 4

20 postmenopausal breast cancer survivors underwent 2 treatments. A follow-up occurred 30 days after the last treatment. The VRS, VHI, FSFI, FSDSr, and a 5- point Likert scale for satisfaction were used to evaluate results.

Microbiome analysis was performed with a vaginal swab.

For the VHI and the FSFI, a statistically significant improvement was

recorded after treatment, while for the FSDSr, no statistically significant improvement was recorded. Regarding the relative proportion of bacteria in the vaginal environment, the Shannon diversity index H and equitability comparison before and after treatment did not yield any

statistically significant results. The relative proportion of bacteria did not differ before and after treatment.

Not specified

(13)

SmartXide² Monalisa Touch, DEKA, (Florence, Italy)

Case Series N=112⁸³ Level 4

112 menopausal women with symptoms of VVA underwent 3 treatments 4 weeks apart. Follow-up occurred 3 months after the last procedure. A VVA symptom questionnaire and the VMI were used to evaluate results.

The median of pre- screening VVA symptom score was 4. There was a significant reduction of the score after laser treatment.

The average percentage of pretreatment VMI was 34.7±16.1% and at one and 3 months after complete laser course, it was significantly increased with the mean change of 25.0±12.2% and

34.8±15.5%, respectively.

No

SmartXide² V²LR;

Prospective Descriptive Cohort N=50⁸⁴ Level 2

50 patients with dyspareunia and

oncological menopause underwent 3 treatment sessions at time points of application at baseline (T1), at 30 days (T2) and at 60 days (T3). The mean follow-up time was 11 months. The VHI, VAS, and a 5-point Likert scale

Data from the VAS indicated a significant improvement in VVA dyspareunia

(p < 1.86e−22). VHI scores were significantly higher 30 days post-treatment (T4) (p < 0.0001). 76% of patients were satisfied or very satisfied with the treatment results. 52% of

No

(14)

were used to evaluate results.

patients were satisfied after a long term follow-up (mean time 11 months).

Retrospective Cohort N=122⁸⁵ Level 3

368 patients who

completed 3 treatments 40- 50 days apart were

contacted by telephone, 122 agreed to be

interviewed. Patients were contacted a mean 31.7+-21 weeks after their final treatment. Patients were asked to complete a 10- point Likert scale for vaginal dryness, frequency of intercourse, results satisfaction, and financial satisfaction.

Patient reported vaginal dryness significantly improved from 8.1 to 4 following treatment (P < 0.05). The frequency of intercourse increased from “once a month” to

“few times a month”

(P < 0.001). 86% of

patients were satisfied with their results and 49% were very satisfied. Satisfaction with the out-of-pocket expense did not correlate with household income (P = 0.07).

5 patients reported urinary tract symptoms, 2 reported vagina pain/burning, 1 reported vaginal itching, and 1 reported dyspareunia.

CO2RE Intima, Syneron Candela, (Wayland, MA)

Prospective N=21⁸⁶ Level 4

21 perimenopausal women with irregular menstrual patterns and symptoms of VVA underwent 3

treatments. A baseline assessment was taken,

At 12 weeks following the third treatment, 82% of the patients showed a

statistically significant improvement in the VHI (P<0.05). Additionally,

Immediate

responses included burning (20%), itching (20%), bruising (4%), swelling (4%),

(15)

and follow-ups occurred at 6, 12, and 24 weeks. The VHI, VAS, and a 5-point Likert scale for sexual function, satisfaction and improvement were used to evaluate results.

81% of subjects reported improvement in sexual gratification, 94% reported improvement in vaginal rejuvenation, and 100%

reported satisfaction with treatment. VHI

improvement remained significant at 6–8 months after treatment (P<0.01).

twinging sensation (4%), numbness (4%) and purpura (2%). 1 patient experienced a mild urinary infection that resolved after a weekly course of antibiotics.

Pilot

Comparative N=70⁸⁷ Level 2

70 patients with symptoms of vestibular pain and vulvodynia (VDB group) (n=37) or GSM (GSM group) (n=33) underwent 3 treatment sessions at least 30 days apart. A baseline assessment was

conducted and follow-ups took place at 4, 8, and 12 weeks after treatment.

Vulvar pain was assessed using a 10-point VAS and dyspareunia was evaluated using the Marinoff and

There was a statistically significant improvement (P<0.05) for the

dyspareunia and pain scores. Improvement was noted with consecutive sessions and was

maintained throughout the 4 month follow-up. The vestibular health index score improved in both groups after each treatment. There was no statistically significant difference in outcomes

Transient burning sensation that resolved within 5-6 days.

(16)

Turner grading system.

Vaginal pain was assessed with a Q tip test, vestibular health and treatment efficacy were evaluated using 4-point scales.

between the VBD group versus the GSM group.

35.2% of the VBD group reported “very improved”, 32.4% “improved”, and 32.4% reported no change.

SmartXide² V²LR;

Prospective Observational N=10⁸⁸

Level 4

10 postmenopausal women with SUI underwent 3 treatments every 3 weeks.

The follow-up period was 6 months. The UDI-6 was used to evaluate symptoms before and after treatment.

The mean score of the UDI-6 before treatment was 37.05 and after treatment it was 15.39.

This indicates subjective improvement in symptoms related to SUI.

Not specified

Case Series N=386⁸⁹ Level 4

386 menopausal women with symptoms of VVA underwent 3 treatments. A VAS was filled out before the first and after the second and third treatment pertaining to symptoms of laxity, dryness, irritation, burning and dyspareunia.

were treated. Menopausal

After 3 treatments, results from the VAS that patients filled out showed

improvement of dryness in 59.94% of patients, burn sensation in 56.26%, dyspareunia in 48.75%, itch in 56.37%, soreness in 73.15%, and vaginal introitus pain in 48.79%.

Mild discomfort with insertion of the probe, minimal blood-serum secretions for 1-2 days, and mild burning sensations for 1-2 hours after treatment were reported.

(17)

women affected with vulvovaginal atrophy (VVA) were treated with three sessions of fractional micro-ablative CO2 laser.

SmartXide² V²LR;

Observational Retrospective N=26⁹⁰

Level 4

26 women affected by hormone-receptor positive breast tumors who also exhibited VVA symptoms underwent 3 treatments every 30-40 days. During each cycle, women completed VAS

questionnaires designed to assess the degree of symptoms and procedure- related discomfort.

Treatment resulted in a significant regression of VVA symptoms and procedure-related

discomfort versus baseline (P < 0.001 in almost all cases). After 3 sessions, the median VAS scores for dyspareunia, dryness, itching/stinging, and sensitivity during sexual intercourse were 78%, 80%, 75%, and 86%, respectively, lower than baseline. Median VAS scores for dysuria and flatulence/leukorrhea were 100% lower after 3

sessions.

Discomfort with insertion of the probe.

(18)

SmartXide² V²LR;

Retrospective N=82⁹¹

Level 4

82 subjects who survived breast cancer, underwent tumor surgery, and had symptoms of VVA

underwent 3 treatments 30- 40 days apart. A VAS was used to assess severity of VVS symptoms and discomfort during procedure.

At baseline, VAS values showed that 88% of patients reported reduced sensitivity during sexual intercourse, 98% reported dyspareunia and

genitourinary symptoms, 56% reported vaginal laxity, 60% reported vaginal discharge, flatulence and/or

leucorrhea, 94% reported vaginal itching/stinging, 68% reported vaginal bleeding, 65% reported dysuria, and 100%

reported vaginal dryness.

After the 3 sessions the symptoms reduced to, respectively, 74%, 80%, 43%, 45%, 65%, 45%, 41%, and 83%. Pre versus post-treatment differences in mean VAS scores were significant for sensitivity

3 subjects discontinued treatment after two cycles because of persistent

procedure-related discomfort, Mild pain with insertion of probe.

(19)

during sexual intercourse, vaginal dryness,

itching/stinging,

dyspareunia and dysuria (P < 0.001 for all), bleeding (P = 0.001), probe insertion (P = 0.001), and movement- related pain (P = 0.011).

SmartXide² V²LR;

Prospective Observational Pilot

N=30⁹² Level 4

30 postmenopausal women who had 1 or more

symptoms related to VVA and had symptoms of OAB underwent 3 treatments at 30-day intervals. At

baseline and 30 days post- treatment, the VHI and VAS for VVA symptoms were used to evaluate results.

There was a statistically significant improvement in VAS scores including dryness (8/3 vs. 2/1.25;

p<0.0001), burning (8/2.25 vs. 1/1 p<0.0001), itching (8/2 vs. 1/1 p<0.0001), and dyspareunia (9.5/1.25 vs.

2/1.25; p<0.0001). There was also a significant improvement in VHI scores (11/3 vs. 22/3.25;

p<0.0001), micturition diary (10/2.5 vs. 6/2;

p<0.0001), number of urge episodes (3/1 vs. 0/1;

No

(20)

p<0.0001), and in OAB-q (18.5/4.25 vs 8/2.25;

p<0.0001).

SmartXide² V²LR;

Pilot N=15⁹³ Level 4

15 postmenopausal subjects with dyspareunia related to VVA underwent 3 treatments. A baseline measurement was taken and follow-ups occurred 1 week, 4 weeks, 8 weeks, and 12 weeks from the third treatment. The VHIS, VAS for VVA symptoms, SF-12, FSFI, PCS12, MCS12, and a 5-point Likert scale for satisfaction were used to evaluate outcomes.

The mean intensity of dyspareunia significantly improved between baseline (8.7±1.0), T2, T3 and 12 weeks (p<0.001). A significant improvement was reported between baseline and 12 weeks in all FSFI domains

(p<0.001). For VHI scores, when compared with baseline, all VVA symptoms significantly improved at week 12 (p<0.05). PCS12 and MCS12 scores significantly improved compared to baseline. At 12 weeks, 40% of patients were very satisfied and 60% were

No

SmartXide² V²LR;

Prospective Cohort

40 women with a history of breast cancer and

77.5% reported satisfaction with the

No

(21)

N=40⁹⁴ Level 2

symptoms of VVA underwent 5 laser applications at 4-week intervals. Follow-ups occurred at 20 weeks. The VHI, SF-12, and FSFI were used to evaluate outcomes.

procedure at the time of follow-up. At 20 weeks, treatment was proven effective to improve VVA symptoms (p<0.001), VHI scores (p<0.001), quality of life scores (SF-12) (p<0.001), as well as FSFI scores (p<0.001).

SmartXide² V²LR;

Prospective Observational N=53⁹⁵

Level 4

53 postmenopausal women with moderate to severe symptoms of GSM

underwent 3 treatments at monthly intervals.

Participants were

evaluated at baseline and 4 weeks after the last

treatment. The VMV, VHIS, FSFI, ICIQ-FLUTS, ICIQ-UI SF, UDI-6, and KHQ were used to evaluate outcomes.

The VMV and VHIS increased significantly. At the baseline none of the participants had

VMV > 49% and VHIS > 15. At the 12- weeks’ follow-up 57% and 89% of the participants had VMV > 49% and VHIS > 15,

respectively. Results from the FSFI showed that at baseline, severe and moderate intensity of VVA- symptoms was 49% and 51%, respectively. At 12-

Temporary mild irritation to the introitus that lasted up to 2 hours after treatment.

(22)

weeks follow-up, severe, moderate, mild and zero intensity of the VVA- symptoms was 2%, 13%, 51% and 34%,

respectively. Lower urinary tract symptoms assessed by the ICIQ-FLUTS, UDI-6, ICIQ-UI SF and KHQ improved significantly as seen by the reduction of these scores. At the baseline 40%, 34%, 23%

and 4% of the participants passed urine during the day 1–6, 7–8, 9–10 and

≥13 times, respectively. At the 12-weeks’ follow-up 47%, 47%, 4% and 2%

passed urine during the day 1–6, 7–8, 9–10, and 11–12 times, respectively.

The change of KHQ questionnaire was >5 points in all participants.

(23)

SmartXide² V²LR;

Retrospective Case Control N=50⁹⁶

Level 3

50 postmenopausal women with GSM and severe dyspareunia and dryness underwent 1 treatment at a monthly interval for 3 months. Either 30 or 40W was used for treatment.

Outcomes were evaluated at baseline and 1 month following the 3rd therapy.

25 women per group (30 vs. 40W) were randomly selected. The FSFI, VMV, and VHIS were used to evaluate results.

In the 30-W group, the mean improvement of dyspareunia, dryness, itching/burning, FSFI, VMV, and VHIS was 6.1 ± 1.7, 6.0 ± 1.9, 5.9 ± 2.0, 16.6 ± 6.7, 29.9 ± 13.0, and 11.0 ± 2.9, respectively (within group comparisons all p < 0.001). In the 40-W group, the mean

improvement of dyspareunia, dryness, itching/burning, FSFI, VMV, and VHIS was 6.1 ± 1.7, 6.5 ± 2.0, 5.2 ± 2.5, 14.8 ± 7.1, 25.0 ± 13.4, and 10.5 ± 4.1, respectively (within-group comparisons, all p ≤ 0.001). Comparison between 30 and 40 W revealed that mean improvement or presence

Adverse events in both groups related to the treatment were irritation and burning sensation with mild intensity at the introitus.

Serious adverse events were not present in any of the participants of either group.

(24)

of all GSM symptoms and clinical signs was not statistically significant different.

SmartXide² V²LR;

Pilot N=50⁹⁷ Level 2

Biopsies were performed before and after treatment on 5 of 50 postmenopausal women with VVA who underwent 3 treatments over 12 weeks.

There were microscopic and ultrastructural modifications of vaginal mucosa following

treatment. There was an observed restoration of the vaginal thick squamous stratified epithelium with a significant storage of glycogen in the epithelial cells and a high degree of glycogen-rich shedding cells at the epithelial surface. The

morphological findings support the effectiveness of fractional CO2 laser application for the restoration of vaginal mucosa structure and

Not specified

(25)

related physiological trophism.

FemiLift, Alma Lasers (Buffalo Grove, IL)

Prospective N=15⁹⁸ Level 4

15 subjects with symptomatic GSM underwent 3 treatment sessions during an 8-week period. 2 weeks after each treatment, subjects

completed the same panel of assessments as at baseline. Subjects were also scheduled to return for additional follow-up at 1 year after the initial treatment. The VABQ, SAVQ, VASQ, PISQ-12, BVHI, VHG and UDI-6 were used to evaluate outcomes.

Comparisons were made between subject's pre and post-treatment

evaluations. Subjects had significant improvements on all 4 of the subjective assessments of GSM and the associated symptoms, which included the VABQ, SAVQ, VASQ, and PISQ- 12 (p=0.0001, p=0.0001, p=0.0002, and 0.0045, respectively). Subjects also showed significant improvement on the BVHI and VHG (p=0.0005 and p=0.0001, respectively).

Subjects did not have significant improvement on the UDI-6 (p=0.2519).

Not specified

SmartXide², MonaLisa Touch,

Randomized Double-blind,

45 postmenopausal women were randomized in laser (L), estriol (E), or laser and

The VHI average was significantly higher at weeks 8 and 20 in all study

No

(26)

(Florence, Italy)

Placebo- Controlled N=45⁹⁹ Level 1

estriol (L+E) groups.

Assessments were made at baseline, 8 and 20 weeks. The VHI, VAS for VVA symptoms, FSFI and VMV were used to evaluate outcomes.

arms. At week 20, the LE arm also showed

incremental improvement of the VHI score (P = 0.01). L and LE groups showed a significant improvement of

dyspareunia, burning, and dryness, and the E arm only of dryness (P <

0.001). The LE group presented significant improvement of the total FSFI score (P = 0.02) and individual domains of pain, desire, and lubrication. In contrast, the L group showed significant

worsening of pain domain in the FSFI (P = 0.04), but FSFI total scores were comparable in all treatment arms at week 20.

(27)

SmartXide² V²LR;

Prospective N=102⁷¹ Level 4

102 postmenopausal women with symptomatic GSM underwent 3

treatments at intervals of 6 or more weeks. Follow-up was approximately 12 months after the initial treatment. The Australian Pelvic Floor Questionnaire was used to evaluate results.

84% percent of subjects experienced significant improvement in their symptoms after treatment.

The median severity score decreased from pretreatment (Md=2) to post- treatment (Md=0). Scores on measures of sexual function, dyspareunia, and sexual issues showed improvement from

pretreatment to long term (12–24 month) follow-up.

Furthermore, there were improvements on

measures of bladder function (P = 0.001), prolapse (P = 0.001), vaginal sensation (P = 0.001), vaginal lubrication (P < 0.001) and urge incontinence (P = 0.003) from the pretreatment assessment to

3 subjects

experienced post- coital urinary tract infections and 2 experienced vaginal

discharge/infection.

3 subjects experienced lower pelvic

pain for 2-3 days. 1 patient (who failed to disclose her past medical history of genital herpes) had a genital herpes breakout following treatment. 2 women presented with

postmenopausal bleeding following their 3rd laser treatment (at 4

(28)

the second assessment (i.e. after the third treatment).

months and 6 months respectively).

SmartXide² V²LR;

Prospective N=77¹⁰⁰ Level 4

77 postmenopausal women with symptoms of VVA underwent 3 treatments at an increment of 4 weeks.

Baseline measurements were taken and a follow-up occurred at 12 weeks from the first treatment. The FSFI, VAS, SSQ and SF- 12 were used to evaluate results.

There was a significant improvement in the total score of the FSFI at 12- week follow-up compared to baseline (p< 0.001). The overall satisfaction with sexual life significantly improved (p< 0.001). 85%

of not sexually active women because of VVA severity at baseline, regained a normal sexual life at the 12-week follow- up. There was a significant improvement shown for each VVA symptom (p <

0.001) and in quality-of-life evaluation on the SSQ, both for the scores in the physical (p = 0.013) and

Not specified

(29)

mental (p = 0.002) domains.

SmartXide² V²LR;

Observational Pilot

N=48¹⁰¹ Level 4

48 postmenopausal patients with one or more VVA-related symptom underwent 3 treatments spaced over 30 days. At baseline (T0) and 30 days post-treatment (T1), vaginal status of the women was evaluated using the VHI and

subjective intensity of VVA symptoms was evaluated using a visual analog scale VAS. At T1, treatment satisfaction was evaluated using a 5-point Likert scale.

There was a significant improvement in VVA symptoms (vaginal dryness, burning, itching and dyspareunia)

(P < 0.0001). VHI scores were significantly higher at T1 (P < 0.0001). Overall, 91.7% of patients were satisfied or very satisfied with the procedure and experienced considerable improvement in quality of life.

No

Two Center Prospective N=30¹⁰²,¹⁰³ Level 4

30 subjects with GSM underwent 3 treatments with 6 weeks (±1 week) between. Follow-ups occurred at 3 months and 1 year after the final

treatment. The VHI, VAS

The average improvement in VAS scores for all symptom categories was statistically significant at 3 months and remained so through 1 year, except dysuria. Differences

Mild to moderate pain posttreatment was reported in 2 patients. Pain resolved within 2 or 3 days. Slight bleeding for less

(30)

rating of all six VVA

symptom categories, FSFI, SF-12, and a complete satisfaction survey assessing perception of results using a 5-point Likert Scale were used to evaluate outcomes.

between data at 3 months and 1 year were not statistically significant, indicating persistence of positive outcomes. The average overall

improvement in pain was 1.9 (±3.4), burning 1.9 (±3.1), itching 1.4 (±1.9), dryness 5.9 (±2.8), dyspareunia 4.9 (±3.3), and dysuria 0.9 (±3.1).

Improvement in the average VHI and FSFI scores was also

statistically significant (P <

0.0001). 22 of 24 women (92%) were satisfied or extremely satisfied with the treatment at 1 year.

than 1 day occurred in 2 patients.

Case Control Observational Study

N=92¹⁰⁴ Level 2

92 patients with symptoms of mild to moderate VA were included in the study and divided into 2 groups.

The study group (n=40)

In the study group, there was a 67.5% improvement in vaginal dryness, a 62.5% improvement in dyspareunia, and a 50%

6 cases of vaginal bleeding occurred with the application of PRP. 30% of patients reported

(31)

underwent PRP (platelet rich plasma) application, CO2 laser treatment, and pelvic exercise training, whereas only PRP and pelvic exercise training were applied to the control group. The study group received PRP 14 days before the laser treatment and biopsies were taken 30 days after the laser

treatment. This protocol was repeated 3 times at an interval of 14 days. The control group underwent PRP every 60 days for 3 sessions. A sexual health questionnaire and vaginal biopsies were used to evaluate results.

improvement in irritation sensation noted on the sexual health

questionnaire. In the control group, there was a 23% improvement in vaginal dryness, a 15.4%

improvement in

dyspareunia, and a 19.2%

improvement in irritation sensation noted on the sexual health

questionnaire. Histological changes in the study group from beginning to the end of treatment indicated a significant increase in the fibrillar component of the extracellular matrix and fibroblast activity bins.

Neoangiogenesis was observed. The thickness of the vaginal epithelium was also increased after laser treatment.

mild discomfort such as pain or a burning sensation with the vaginal scanner

application.

(32)

SmartXide² V²LR;

Prospective N=53¹⁰⁵ Level 4

53 postmenopausal women underwent 3 monthly treatments. Before each laser application, a sterile swab was inserted into the vaginal canal and a sample was obtained from the posterior fornix of the vagina.

Laser therapy increased Lactobacillus (p < 0.001) and normal flora (p <

0.001) after the completion of the therapeutic protocol, which decreased vaginal pH from a mean of 5.5 ± 0.8 (initial value) to 4.7 ± 0.5 (p < 0.001). The prevalence of

Lactobacillus changed from 30% initially to 79%

after the last treatment.

Clinical signs and symptoms of bacterial vaginosis, aerobic vaginitis or candidiasis did not appear in any participant.

No

SmartXide² V²LR;

Pilot Study N=50¹⁰⁶ Level 4

50 postmenopausal women with VVA underwent 3 treatments over 12 weeks.

The VHIS, VAS, PSC12, MCS12, and SF-12 were used to evaluate results.

Significant improvement in the VHIS as well as the PSC12 and MCS12 measures (SF-12) were reported. 84% of patients reported satisfaction with the procedure. At 12

No

(33)

weeks follow-up, VVA symptoms (vaginal dryness, vaginal burning, vaginal itching,

dyspareunia, dysuria showed significant

improvement (p < 0.001).

The VHIS showed significant improvement from 13.1+-2.5 at baseline vs. 23.1+-1.9 (p<0.001).

SmartXide² V²LR;

Prospective N=386¹⁰⁷ Level 4

386 menopausal subjects underwent 3 monthly treatments. A VAS was used to asses laxity symptoms, vaginal

dryness, irritation, burning, and dyspareunia.

2 months post-completion of the final treatment, 59.94% of patients reported a reduction in vaginal dryness, 56.26%

reported a reduction in vaginal burning sensation, 48.75% reported

improvements in dyspareunia, 56.37%

reported improvements in itch, 73.15% reported reductions in soreness, and 48.79% reported a

A burning sensation, discomfort during handpiece

movement, vulvar introitus

burning/pain, and vulvar pain were reported.

(34)

reduction in vaginal introitus pain.

SmartXide² V²LR;

Prospective, N=161¹⁰⁸ Level 4

161 postmenopausal subjects with a clinical diagnosis of mild SUI underwent 1 treatment every 30–45 days for 4 sessions followed by a yearly treatment session at 12, 24 and 36 months. A 1- hour pad test and the ICIQ- UI SF were used to

evaluate results.

Treatment was associated with a significant

improvement in ICIQ-UI SF scores and 1-h pad weight test at 12 months, 24 months, and 36 months (p < 0.001). Improvements were maintained for up to 36 months without the need for any further intervention.

No

Comparative Study

Device Name Type of Study Methods Results Adverse Side

Effects FotonaSmooth

(XS Dynamis), (Dallas, TX) and

SmartXide², MonaLisa Touch,

Prospective N=31¹⁰⁹ Level 2

31 subjects with SUI

underwent 1 laser treatment.

21 patients were treated with an Er:YAG laser and 10 were treated with a CO2

laser. Baseline

measurements were taken and a follow-up occurred at

Both patients in the Er:YAG laser group and the CO2 laser group showed significant improvement in SUI symptoms and quality of life (ICIQ-SF scores, Er:YAG laser 8.25 ± 5.66

Mild irritation of the introitus was noted during the procedure but resolved spontaneously after therapy.

(35)

(Florence, Italy)

2 months post treatment. A 1-hour pad test and the FSFI and ICIQ-SF were used to evaluate results.

to 5.00 ± 3.99, P = 0.007, CO2 laser 11.11 ± 6.85 to 6.44 ± 4.25, P = 0.035).

Patients treated with the Er:YAG laser did not show improvement in FSFI total scores (48.22 ± 20.28 versus 46.11 ± 22.02, P = 0.775), while patients treated with the CO2 laser showed little improvement in FSFI total scores (28.5 ± 29.69 versus 31.17 ± 30.86, P = 0.066).

The 1-hour pad weight tests showed improved scores from both groups (Er:YAG laser 3.42 ± 6.31 to 1.48 ± 3.18, P = 0.139, CO₂laser 2.71 ± 4.98 to 1.74 ± 3.56, P = 0.593), although the results were not statistically significant.

*Side effects per specific device were not distinguished

(36)

Scoring and Self-Reported Questionnaires for CO₂Devices:

Urogenital Distress Questionnaire, Sexual Satisfaction Questionnaire (SSQ), Pelvic Organ Prolapse Questionnaire, King's Health Questionnaire (KHQ), Visual Analog Scale (VAS), International Consultation on Incontinence Questionnaires- Female Urinary Tract Symptoms (ICIQ-FLUTS), International Consultation on Incontinence Questionnaires-Urinary Incontinence Short Form (ICIQ- UI SF), International Consultation on Incontinence Questionnaires-Urinary Incontinence Short Form (ICIQ- UI), Urogenital Distress Inventory-6 (UDI-6), Female Sexual Function Index (FSFI), Vaginal Health Index (VHI), Vaginal Maturation Index (VMI), Patient Global Impression of Improvement (PGI-I), Vaginal Maturation Value (VMV), Vaginal Health Index Score (VHIS), Wong-Baker Faces Scale (WBFS), Short Form (SF-12), Symptoms of Atrophic Vaginitis Questionnaire (SAVQ), Vulvovaginal Atrophy Symptom Questionnaire (VASQ), International Consultation on Incontinence Questionnaire (ICIQ-UI), Day-by-day Impact of Vaginal Aging (DIVA), Vulvo-Vaginal Health Index (VVHI), Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), Vaginal Atrophy Bother Questionnaire (VABQ), Australian Pelvic Floor Questionnaire, Female Sexual Distress Scale Revised 2005 (FSDSr), Verbal Rating Scale (VRS), Marinoff and Turner grading system, Physical Component Summary (PCS12), Mental Component Summary (MCS12) Bachman Vaginal Health Index (BVHI), Vaginal Health Grade (VHG)