Objectives: This study aimed to evaluate the vagina clinically, cytologically, and histologically before and after treating genitourinary syndrome of menopause (GSM) with fractional microablative carbon dioxide LASER (CO2L), radiofrequency (RF), and estrogen vaginal cream (CT). Methods: Women with moderate-to-severe symptoms of GSM, denoted by a GSM Visual analog scale (VAS) score of >4, were eligible for this study. The patients were randomized into treatment groups. In the energy groups, three vulvovaginal applications were administered monthly. The CT group used 0.5 mg vaginal estriol cream for 14 consecutive days, followed by twice a week for 4 months. The follow-up visits occurred 120 days after the beginning of the treatments. The same parameters obtained at the first visit were re-evaluated: GSM VAS score, Incontinence Quality of Life Questionnaire (I-QOL), gynecological examination determining Vaginal Health Index (VHI), vaginal smear for Vaginal Maturation Value (VMV), and vaginal biopsy. Results: Seventy-one women were included, 48 completed the study and provided adequate samples for analysis (CO2L [21 patients], RF [15 patients], and CT [12 patients]). GSM symptoms, I-QOL, and VHI significantly improved after all proposed treatments, with no significant differences between them. VMV did not change after any treatment; however, only 22.9% of the patients presented with cytological atrophy before treatment. Histological vaginal atrophy was identified in 6 (12.5%) pretreated vaginal samples. After the intervention, all histological parameters were normalized, no tissue damage was observed, and no major clinical complications were observed. Conclusion: CO2L and RF seem to be good alternatives to CT for GSM treatment, with no tissue damage.
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