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Innovative therapies in gynecology: The evidence and your practice
As more and more gynecologic therapies move to the outpatient setting, keeping up on the latest data regarding emerging options can be challenging. Furthermore, it can be difficult to justify purchasing expensive equipment for the office when a therapy is not covered by medical insurance plans. However, if a therapy is efficacious and patients are willing to pay out of pocket, clinicians may want to have these options available for their patients.
In an effort to work through these complex issues, a panel of experts was convened at the 47th Annual Scientific Meeting of the Society of Gynecologic Surgeons in Palm Springs, California, on June 29, 2021. This article includes the salient points from that panel discussion.
Fractionated CO2 laser therapy
Fractionated CO2 laser therapy is considered second-line therapy for the treatment of genitourinary syndrome of menopause (GSM). In 2018, the US Food and Drug Administration (FDA) issued a safety warning about the use of CO2 laser therapy and warned patients and clinicians that the FDA had not approved the treatment for vaginal rejuvenation or treatment of vaginal symptoms related to menopause, urinary incontinence, or sexual function. Despite this warning, laser treatments are still performed in many practices.
In 2019, the International Continence Society (ICS) and the International Society for the Study of Vulvovaginal Disease (ISSVD) put out a joint practice consensus statement that essentially did not recommend the routine use of laser treatment for GSM, urinary incontinence, or lichen sclerosus.1 Conversely, the 2020 American Urogynecologic Society (AUGS) published a clinical consensus statement that spoke to the promising results of laser therapy for the treatment of vulvovaginal atrophy, vaginal dryness, and menopausal dyspareunia, with benefits lasting up to 1 year.2 This statement also suggested that the short-term safety profile of the CO2 laser device was favorable.
How CO2 lasers work
Fractionated CO2 laser therapy differs from unfractionated treatment (which often is used in the treatment of condyloma) in that it is not ablative. The laser works by using fractionated beams of light to penetrate the affected tissue to create small wounds in the epithelium and underlying lamina propria, which leads to collagen remodeling and regeneration that then results in the restoration of the superficial epithelium, vaginal rugae, and lubrication.3 Most clinicians perform 3 applications of the laser treatment 6 weeks apart, a recommendation that is based on manufacturer-sponsored studies in menopausal women.
Study results of patient outcomes with laser therapy
GSM. Several retrospective4,5 and prospective studies6-10 have looked at short- and longer-term outcomes in patients undergoing treatment with the CO2 laser. All of these studies showed improvement in patient symptoms related to GSM.
The VeLVET trial, conducted by Paraiso and colleagues, was a randomized trial that compared CO2 laser treatment with vaginal estrogen in women with GSM.11 While the study was underpowered due to cessation of enrollment once the FDA safety warning was issued, the authors reported that at 6 months, both the fractionated CO2 laser therapy group and the vaginal estrogen group had similar improvements, with 70% to 80% of participants reporting satisfaction with treatment. The authors concluded that laser therapy is likely to be as efficacious as vaginal estrogen and may be a good option for patients who cannot use vaginal estrogen to treat GSM.11
Lichen sclerosus. Some data exist on the efficacy of laser therapy for the treatment of lichen sclerosus. One recently published randomized trial showed that at 6 months, fractionated CO2 laser treatment and prior treatment with high potency topical corticosteroids was associated with higher improvement in subjective symptoms and objective measures compared with clobetasol propionate treatment.12 Another trial, however, revealed that laser treatment was not an effective monotherapy treatment for lichen sclerosus when compared with placebo.13 Fewer studies have examined the effect of laser therapy on urinary incontinence.
More prospective data are emerging, evidenced by trials currently registered in ClinicalTrials.gov. While some studies provide evidence that laser therapy may be efficacious in the treatment of vulvovaginal atrophy, additional data are needed to confirm the favorable outcomes observed with laser therapy for the treatment of lichen sclerosus, and a significant amount of data are needed to evaluate the efficacy of laser treatment for urinary incontinence.
Until such evidence is available, fractionated CO2 vaginal laser therapy will remain a fee-for-service treatment option and will be inaccessible to patients who cannot afford the cost of treatment.
Continue to: Hydrogel urethral bulking...
Hydrogel urethral bulking
Urethral bulking agents have been used for 5 decades in the treatment of stress urinary incontinence (SUI) in women. Unlike midurethral slings, in which many medical device companies use the same implant material (microporous, monofilament polypropylene mesh), the material for bulking agents has varied greatly. A 2017 Cochrane review of urethral bulking listed these agents used for this indication: autologous fat, carbon beads, calcium hydroxylapatite, ethylene vinyl alcohol copolymer, glutaraldehyde cross-linked bovine collagen, hyaluronic acid with dextranomer, porcine dermal implant, polytetrafluoroethylene, and silicone particles.14 These agents can be injected through a transurethral or periurethral technique. The review failed to find superiority of one material or injection technique over another.
New bulking agent available
In January 2020, the FDA approved the premarket application for a new bulking agent. This new agent is a permanently implanted, nonresorbable hydrogel that consists of cross-linked polyacrylamide (2.5%) and water (97.5%). It is intended to be used with a transurethral bulking system that includes a rotatable sheath and two 23-guage needles; a total of 1.5 to 2.0 mL of the hydrogel is injected in 3 locations in the proximal urethra per session. Patients may undergo an additional 2 sessions, if needed, at least 4 weeks after the previous session.
Polyacrylamide hydrogel has been used as a bulking agent in cosmetic and ophthalmic surgery for many years, and it was first approved for medical use in Europe in 2001. The initial European data on its use as a urethral bulking agent was published in 2006.15 The first North American data came in 2014 from a multicenter, randomized trial that compared polyacrylamide hydrogel with collagen gel.16 This investigation followed 345 women for 12 months and concluded that the safety and efficacy of polyacrylamide hydrogel was not inferior to collagen, with a little over half of both cohorts demonstrating a 50% or greater decrease in incontinence episodes.
Since these initial studies, 3-year17 and 7-year safety and efficacy data18 have been reported, with reassuring findings, but both studies experienced significant attrition of the original group of patients. The most commonly reported adverse events associated with the procedure are pain at the injection site (4%–14%) and urinary tract infection (3%–7%); transient urinary retention rates range in incidence from 1.5% to 15%.19
Short procedure, long-term results
Given that a urethral bulking procedure can be done in less than 10 minutes in the office under local analgesia, this treatment may lend itself to use in more brittle patient populations. One study of women aged 80 or older showed a greater than 50% decrease in the number of daily pads used for up to 2 years after initial injection.20 Another study found the greatest treatment success in women aged 60 years or older with fewer than 2.5 episodes of SUI per day.21
Platelet-rich plasma therapy
Platelet-rich plasma (PRP) therapy has been used in multiple disciplines for more than 2 decades as a treatment to regenerate damaged tissue, particularly in sports medicine for treating tendonitis as well as in plastic surgery, gynecology, urology, and ophthalmology, and good outcomes have been demonstrated with no serious adverse effects. PRP is a natural product in which high levels of platelets are concentrated through centrifugation with bioactive growth factors, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and insulin growth factor (IGF).22 The activated platelets are then injected autologously back into the patient’s tissue. This process releases activated growth factors that accelerate tissue healing by stimulating the number of reparative cells to create collagen production, angiogenesis, and neurogenesis while fighting infection and downregulating the autoimmune system.
Continue to: Uses for PRP in gynecology...
Uses for PRP in gynecology
In gynecology, dating back to 2007 PRP was shown to facilitate wound healing, when Fanning and colleagues reported PRP applications in gynecologic operative wounds, such as hysterectomies and urogynecologic procedures, to reduce postoperative pain.23 In the last decade, there has been a dramatic increasing trend in the application of PRP injections as an alternative therapy in gynecology to improve intimate health. PRP has been used to treat lichen sclerosus, atrophic vaginitis, SUI, and female sexual dysfunction; however, there is a dearth of studies that compare PRP with traditional therapies.
Runels and colleagues described the effects of localized injections of autologous PRP for the treatment of sexual dysfunction early in 2014.24 Those authors pioneered PRP use in women with dyspareunia and other symptoms related to sexual dysfunction. Women were offered PRP injections into the periurethral area of the Skene glands and the clitoris. Sexual satisfaction and pain were improved but results did not reach statistical significance. The results of this pilot study of 11 patients suggested that PRP injections could perhaps be an effective method to treat certain types of female sexual dysfunction, including desire, arousal, lubrication, and orgasm.
In another pilot study, Long and colleagues looked at the effectiveness of local injection of PRP for treating women with SUI.25 In that study, younger patients with mild severity of SUI had promising results, with up to 75% cured or improved. Results in the older group, with 50% cured or improved, did not reach statistical significance. Other small, limited studies have been conducted under the hypothesis that PRP as an “O-shot” may be a promising treatment that is a safe, effective, nonsurgical, and nonhormonal option for women with dyspareunia from lack of lubrication and related sexual dysfunction, such as decreased libido or arousal.26-29 A pilot study by Behnia-Willison and colleagues demonstrated clinical improvement in PRP use as an alternative to topical steroids for lichen sclerosus.30 Several other studies also have shown efficacy for the treatment of lichen sclerosus.31-34
More evidence of efficacy needed
To date, preliminary studies suggest that PRP holds promise for a host of gynecologic conditions. Since PRP is autologous, there are no significant contraindications, and thus far there have been no known serious adverse effects. However, most health insurers still do not cover this therapy, so for now patients must pay out-of-pocket fees for these treatments.
As we continue to investigate therapies in regenerative medicine, the continued efforts of our discipline are required to conduct well-designed prospective, randomized controlled studies. While initial series suggest that PRP is safe, it is unlikely that this therapy will be embraced widely in the paradigm as an alternative treatment option for many genitourinary symptoms of menopause and vulvar disorders until efficacy is better established.
Radiofrequency therapy
For the past 20 years, radiofrequency (RF) energy has been used through the vagina, urethra, and periurethral tissues for the treatment of genitourinary symptoms, with limited success. More recently, because some patients hesitate to receive mesh implants for treatment of urinary incontinence,35 there has been gravitation to office-based procedures.
In contrast to lasers, which transmit energy through light, RF waves (measured in hertz) transform the kinetic energy of the intracellular atoms, which move and collide, generating thermal energy.36,37 RF therapy has been shown to increase the proportion of smooth muscle and connective tissue; stimulate proliferation of the epithelium, neovascularization, and collagen formation in the lamina propria; and improve natural lubrication.36,38 In addition, RF is:
- ablative when the heat is capable of generating ablation and/or necrosis of the epidermis and dermis
- microablative when energy fractionation produces microscopic columns of ablative thermal lesions in the epidermis and upper dermis, resulting in microscopic columns of treated tissue interspersed with areas of untreated skin,39 and
- nonablative when trauma occurs only in the dermis by heating without causing ablation of the epidermis.39
The RF devices discussed below are used with settings for microablation in the treatment of SUI and sexual health/vaginal laxity, and with nonablative settings in the treatment of GSM.
RF for the treatment of urinary incontinence
Studies with RF have shown its benefits in urinary symptoms as secondary outcomes, such as improvement of SUI.38,40 One theory that favors energy devices as a treatment for SUI is that the treatment strengthens suburethral and pubocervical support, thereby decreasing urethral mobility.41
In 2016, the Viveve system (Viveve) received FDA 510(k) clearance for “use in general surgical procedures for electrocoagulation and hemostasis.” A single-site, randomized, nonblinded pilot study compared 1 treatment (group 1) versus 2 treatments (group 2) with the Viveve system for SUI in 35 participants.42 At 12 months, only for group 2 did mean scores on the Incontinence Impact Questionnaire Short Form (IIQ-7) and the International Consultation on Incontinence Modular Questionnaire-Urinary Incontinence-Short Form (ICIQ-UI-SF) decrease by the minimum clinically important difference of 16 and 2.52 points, respectively, compared with baseline.
The ThermiVa device (ThermiGen, LLC) received FDA clearance for “use in dermatological and general surgical procedures for electrocoagulation and hemostasis” in 2017. A single-site, prospective, double-blind, randomized controlled pilot trial evaluated the efficacy of this device for the treatment of SUI in 20 participants randomly assigned in a 1:1 fashion to active and sham groups.43 At 12 weeks, mean scores of the Urogenital Distress Inventory (UDI-6) and the ICIQ-UI-SF decreased by the minimal clinically important difference only in the treatment group arm. Additionally, 70% of treatment group participants had a negative stress test at 12 weeks compared with 0% of control group participants.43 In another study of 48 patients who were followed longitudinally for 5 months, a substantial improvement in genital appearance was observed.44 Assessment based on validated instruments demonstrated significant improvements in sexual function and SUI.44
A microablative RF device (Wavetronic 6000 Touch Device, Megapulse HF FRAXX system; Loktal Medical Electronics) consists of a vaginal probe with 64 microneedles at the tip, each capable of penetrating to a depth of 1 mm. During activation, delivery of RF energy, which results in vaporization of tissue at 100 °C, occurs in a preset sequence of 8 needles at a time, preventing the overheating of intervening tissue between adjacent needles.
Slongo and colleagues conducted a 3-arm randomized clinical trial that included 117 climacteric women with SUI.45 In group 1, treatment consisted of 3 monthly sessions of RF; group 2 received 12 weekly sessions of pelvic floor muscle training (PFMT); and group 3 received RF treatment plus PFMT simultaneously. Assessments were conducted at baseline and 30 days after the end of therapy using validated questionnaires and scales for urinary, vaginal, and sexual functions, and cytology was used to assess vaginal atrophy. The association between RF and PFMT showed significant improvement in the SUI symptoms assessed by questionnaire. The vaginal symptoms and dryness showed more substantial improvement with the RF treatment, and vaginal laxity showed similar improvement in the 3 treatment groups.45
Continue to: RF for the treatment of GSM...
RF for the treatment of GSM
For women who are not candidates for localized hormone therapy, as well as others who simply do not wish to use hormones, nonablative RF laser therapy may be an alternative for the management of GSM.
The VIVEVE I trial was one of the largest randomized, sham-controlled trials performed to determine the efficacy of vaginal rejuvenation using surface-cooled RF; 174 women received either RF treatment (90 J/cm2) or sham treatment (1 J/cm2).46 Treated participants had a significant improvement in perception of vaginal laxity/looseness and sexual function up to 6 months posttreatment.46 Overall, participants were satisfied with the treatment (77.8%–100%) and reported significant improvements in vaginal laxity and symptoms of atrophy. RF was well tolerated with minimal adverse effects, such as procedure-related erythema and edema of treated tissue, and vaginal discharge. One patient discontinued treatment because of procedural pain.47,48
The ThermiVa system also was evaluated for efficacy in the treatment of GSM in a single-site, double-blind randomized controlled pilot study, the methods of which were previously described above.43 GSM symptoms were evaluated at baseline and 12 weeks using the Vaginal Health Index (VHI) and visual analog scale (VAS). At the 12-week follow-up, compared with baseline scores, VHI scores were unchanged in the control group and improved in the treatment group. Additionally, VAS scores for dyspareunia decreased in the treatment group compared with baseline while VAS for dyspareunia in the sham group did not change from baseline to 12 weeks.
RF treatment for sexual health
The efficacy of the Viveve RF system for female sexual dysfunction was evaluated in an international, randomized, controlled, single-blinded study (n = 154) that compared 6-month outcomes of RF treatment versus sham treatment.46 Although there was a statistically significant improvement in patient-reported sexual dysfunction on validated instruments, it is essential to note that the study was powered for the primary outcome of vaginal laxity. In addition, the study was not adequately powered to evaluate safety; however, the adverse events reported were mild, and the most frequently reported adverse event was vaginal discharge.
Microablative monopolar RF treatment for GSM has been evaluated in 2 single-arm clinical trials that included a total of 70 patients.39,49 Pre- and posttreatment outcomes were analyzed after delivery of 3 treatment sessions 28 to 40 days apart. Although the only significant improvement in quality of life was in the health domain of the World Health Organization Quality of Life Adapted Questionnaire (P = .04), significant improvements in sexual functioning were seen in terms of the desire (P = .002), lubrication (P = .001), satisfaction (P = .003), and pain (P = .007) domains of the Female Sexual Function Index (FSFI) questionnaire except for excitation and orgasm.39 Overall, 100% of participants reported being satisfied or very satisfied with treatments, and 13 of 14 women felt “cured” or “much better.”39 After treatment, significant increases in vaginal Lactobacillus (P<.001), decreases in vaginal pH (P<.001), improvements in maturation of vaginal cellularity (decreased parabasal cells, P<.001; increased superficial cells, P<.001), and increased VHI score (P<.001) alone occurred.49 No adverse events beyond self-limited vaginal burning and redness were reported.39,49 In another study mentioned above, the combination of RF and PFMT in sexual function does not offer benefits superior to those achieved by the therapies alone.45
Evidence on RF treatment does not support marketing efforts
Radiofrequency devices have been marketed for a variety of genitourinary problems in women, with limited high-quality, randomized, comparative evidence of efficacy and durability in the literature. It is unfortunate that RF treatment continues to be promoted by practitioners around the world who cite small, short-term studies that lack biostatistical rigor in their reporting of protocols and results. Statements from both AUGS and the International Urogynecological Association have heeded caution on the use of lasers but they could not even evaluate RF devices due to lack of evidence.2,41
Informed counseling and shared decision making remain the bottom line
By the year 2025, all members of the Baby Boom generation will be aged 60 or older. While in the past there has been a reluctance to discuss women’s sexual health, urinary incontinence, and GSM, the need for open discussion and a variety of treatment options for these conditions has never been more critical.
Many patients prefer office-based therapies over hospital-based procedures, and others are leery of synthetic implants. These concerns are leading toward great interest in the types of treatments covered in this article. However, it is paramount that clinicians are aware of the evidence-based data behind these emerging options so that we can openly and accurately counsel our patients.
As we have shown, the quality of the data behind these officed-based therapies varies significantly. Until a greater body of research data is available, we must carefully balance our desire to meet patient wishes with solid, informed counseling and shared decision making. ●
- Preti M, Viera-Baptista P, Digesu GA, et al. The clinical role of LASER for vulvar and vaginal treatments in gynecology and female urology: an ICS/ISSVD best practice consensus document. J Lower Genital Tract Dis. 2019;23:151-160.
- Alshiek J, Garcia B, Minassian V, et al. Vaginal energy-based devices: AUGS clinical consensus statement. Female Pelvic Med Reconstr Surg. 2020;26:287-298.
- Streicher LF. Vulvar and vaginal fractional CO2 laser treatments for genitourinary syndrome of menopause: NAMS practice pearl. Menopause. 2018;25:571-573.
- Gardner AN, Aschkenazi SO. The short-term efficacy and safety of fractional CO2 laser therapy for vulvovaginal symptoms in menopause, breast cancer, and lichen sclerosus. Menopause. 2021; 28:511-516.
- Balchander D, Nyirjesy P. Fractionated CO2 laser therapy in recalcitrant lichen sclerosus. J Lower Genital Tract Disease. 2020;24:225-228.
- Pieralli A, Fallani MG, Becorpi A, et al. Fractional CO2 laser for vulvovaginal atrophy (VVA) dyspareunia relief in breast cancer survivors. Arch Gynecol Obstet. 2016;294:841-846.
- Pieralli A, Bianchi C, Longinotti M, et al. Long-term reliability of fractionated CO2 laser as a treatment of vulvovaginal atrophy (VVA) symptoms. Arch Gynecol Obstet. 2017; 296:973-978.
- Sokol ER, Karram MM. Use of novel fractional CO2 laser for the treatment of genitourinary syndrome of menopause: 1-year outcomes. Menopause. 2017;24: 810-814.
- Pagano T, Conforti A, Buonfantino C, et al. Effect of rescue fractional microablative CO2 laser on symptoms and sexual dysfunction in women affected by vulvar lichen sclerosus resistant to long-term use of topic corticosteroid: a prospective longitudinal study. Menopause. 2020;27:418-422.
- Sindou-Faurie T, Louis-Vahdat C, Oueld Es Cheikh E, et al. Evaluation of the efficacy of fractional CO2 laser in the treatment of vulvar and vaginal menopausal symptoms. Arch Gynecol Obstet. 2021;303:955-963.
- Paraiso MFR, Ferrando CA, Sokol ER, at al. A randomized clinical trial comparing vaginal laser therapy to vaginal estrogen therapy in women with genitourinary syndrome of menopause: the VeLVET trial. Menopause. 2019;27:50-56.
- Burkett LS, Siddique M, Zeymo A, et al. Clobetasol compared with fractionated carbon dioxide laser for lichen sclerosus: a randomized controlled trial. Obstet Gynecol. 2021;137:968-978.
- Mitchell L, Goldstein AT, Heller D, et al. Fractionated carbon dioxide laser for the treatment of vulvar lichen sclerosus: a randomized controlled trial. Obstet Gynecol. 2021;136:979-987.
- Kirchin V, Page T, Keegan PE, et al. Urethral injection therapy for urinary incontinence in women. Cochrane Database Syst Rev. 2017;7:CD003881.
- Lose G, Mouritsen L, Nielson JB. A new bulking agent (polyacrylamide hydrogel) for treating stress urinary incontinence in women. BJU Int. 2006;98:100-104.
- Sokol ER, Karram MM, Dmochowski R. Efficacy and safety of polyacrylamide hydrogel for the treatment of female stress incontinence: a randomized, prospective, multicenter North American study. J Urol. 2014;192:843-849.
- Pai A, Al-Singary W. Durability, safety and efficacy of polyacrylamide hydrogel (Bulkamid) in the management of stress and mixed urinary incontinence: three year follow up outcomes. Cent European J Urol. 2015;68:428-433.
- Brosche T, Kuhn A, Lobodasch K, et al. Seven-year efficacy and safety outcomes of Bulkamid for the treatment of stress urinary incontinence. Neurourol Urodyn. 2021;40:502-508.
- Kasi AD, Pergialiotis V, Perrea DN, et al. Polyacrylamide hydrogel (Bulkamid) for stress urinary incontinence in women: a systematic review of the literature. Int Urogynecol J. 2016;27:367-375.
- Vecchioli-Scaldazza CV, Smaali C, Morosetti C, et al. Polyacrylamide hydrogel (Bulkamid) in female patients of 80 or more years with urinary incontinence. Int Braz J Urol. 2014;40:37-43.
- Elmelund M, Sokol ER, Darram MM, et al. Patient characteristics that may influence the effect of urethral injection therapy for female stress urinary incontinence. J Urol. 2019;202:125-131.
- Sanoulis V, Nikolettos N, Vlahos N. The use of platelet-rich plasma in the gynecological clinical setting: a review. HJOG. 2019;18:55-65.
- Fanning J, Murrain L, Flora R, et al. Phase I/II prospective trial of autologous platelet tissue graft in gynecologic surgery. J Minim Invasive Gynecol. 2007;14:633-637.
- Runels CE, Melnick H, DeBourbon E, et al. A pilot study of the effect of localized injections of autologous platelet rich plasma (PRP) for the treatment of female sexual dysfunction. J Womens Health Care. 2014;3:4.
- Long CY, Lin KL, Shen CR, et al. A pilot study: effectiveness of local injection of autologous platelet-rich plasma in treating women with stress urinary incontinence. Sci Rep. 2021;11:1584.
- Matz EJ, Pearlman AM, Terlecki RP. Safety and feasibility of platelet rich fibrin matrix injections for treatment of common urologic conditions. Investig Clin Urol. 2018;59:61-65.
- Neto JB. O-Shot: platelets rich plasma in intimate female treatment. J Womens Health Care. 2017;6:5.
- Nikolopoulos KI, Pergialiotis V, Perrea D, et al. Restoration of the pubourethral ligament with platelet rich plasma for the treatment of stress urinary incontinence. Med Hypotheses. 2016;90:29-31.
- Hersant B, SidAhmed-Mezi M, Belkacemi Y, et al. Efficacy of injecting platelet concentrate combined with hyaluronic acid for the treatment of vulvovaginal atrophy in postmenopausal women with a history of breast cancer: a phase 2 pilot study. Menopause. 2018;25:1124-1130.
- Behnia-Willison F, Pour NR, Mohamadi B, et al. Use of platelet-rich plasma for vulvovaginal autoimmune conditions like lichen sclerosus. Plast Reconstr Surg Glob Open. 2016;4:e1124.
- Goldstein AT, King M, Runels C, et al. Intradermal injection of autologous platelet-rich plasma for the treatment of vulvar lichen sclerosus. J Am Acad Dermatol. 2017;76:158-160.
- Casabona F, Priano V, Vallerino V, et al. New surgical approach to lichen sclerosus of the vulva: the role of adipose-derived mesenchymal cells and platelet-rich plasma in tissue regeneration. Plast Reconstr Surg. 2010;126:210e-211e.
- Franic D, Iternica Z, Franic-Ivanisevic M. Platelet-rich plasma (PRP) for the treatment of vulvar lichen sclerosus in a premenopausal woman: a case report. Case Rep Womens Health. 2018;18: e0062.
- Posey LK, Runels C. In office surgery and use of platelet rich plasma for the treatment of vulvar lichen sclerosus to alleviate painful sexual intercourse. J Lower Genital Tract Dis. 2017;21(4S):S14.
- Stachowicz AM, Hoover ML, Karram MM. Clinical utility of radiofrequency energy for female genitourinary dysfunction: past, present, and future. Int Urogynecol J. 2021;32:1345-1350.
- Tadir Y, Gaspar A, Lev-Sagie A, et al. Light and energy based therapeutics for genitourinary syndrome of menopause: consensus and controversies. Lasers Surg Med. 2017;49:137-159.
- US Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, MD, on efforts to safeguard women’s health from deceptive health claims and significant risks related to devices marketed for use in medical procedures for “vaginal rejuvenation.” https://www.fda.gov/news-events/pressannouncements/statement-fda-commissioner-scott-gottlieb-mdefforts-safeguard-womens-health-deceptive-health-claims. Updated August 2, 2018. Accessed August 13, 2021.
- Vicariotto F, Raichi M. Technological evolution in the radiofrequency treatment of vaginal laxity and menopausal vulvo-vaginal atrophy and other genitourinary symptoms: first experiences with a novel dynamic quadripolar device. Minerva Ginecol. 2016;68:225-236.
- Kamilos MF, Borrelli CL. New therapeutic option in genitourinary syndrome of menopause: pilot study using microablative fractional radiofrequency. Einstein (Sao Paulo). 2017;15:445-551.
- Caruth JC. Evaluation of the safety and efficacy of a novel radiofrequency device for vaginal treatment. Surg Technol Int. 2018;32:145-149.
- Shobeiri SA, Kerkhof MH, Minassian VA, et al. IUGA committee opinion: laser-based vaginal devices for treatment of stress urinary incontinence, genitourinary syndrome of menopause, and vaginal laxity. Int Urogynecol J. 2019;30:371-376.
- Allan BB, Bell S, Husarek K. Early feasibility study to evaluate the Viveve system for female stress urinary incontinence: interim 6-month report. J Womens Health (Larchmt). 2020;29:383-389.
- Leibaschoff G, Izasa PG, Cardona JL, et al. Transcutaneous temperature controlled radiofrequency (TTCRF) for the treatment of menopausal vaginal/genitourinary symptoms. Surg Technol Int. 2016;29:149-159.
- Desai SA, Vakil Z, Kroumpouzos G. Transcutaneous temperature-controlled radiofrequency treatment: improvement in female genital appearance, sexual dysfunction, and stress urinary incontinence. Aesthet Surg J. 2021;sjab174. doi: 10.1093/asj/sjab174.
- Slongo H, Lunardi AL, Riccetto CL, et al. Microablative radiofrequency versus pelvic floor muscle training for stress urinary incontinence: a randomized controlled trial. Int Urogynecol J. 2021. doi: 10.1007 /s00192-021-04758-2.
- Krychman M, Rowan CG, Allan BB, et al. Effect of single-treatment, surface-cooled radiofrequency therapy on vaginal laxity and female sexual function: the VIVEVE I randomized controlled trial. J Sex Med. 2017;14:215-225.
- Zerbinati N, Serati M, Origoni M, et al. Microscopic and ultrastructural modifications of postmenopausal atrophic vaginal mucosa after fractional carbon dioxide laser treatment. Lasers Med Sci. 2015;30: 429-436.
- Juhasz ML, Korta DZ, Mesinkovska NA. Vaginal rejuvenation: a retrospective review of lasers and radiofrequency devices. Dermatol Surg. 2021;47:489-494.
- Sarmento AC, Fernandes FS, Marconi C, et al. Impact of microablative fractional radiofrequency on the vaginal health, microbiota, and cellularity of postmenopausal women. Clinics (Sao Paulo). 2020;75:e1750.
As more and more gynecologic therapies move to the outpatient setting, keeping up on the latest data regarding emerging options can be challenging. Furthermore, it can be difficult to justify purchasing expensive equipment for the office when a therapy is not covered by medical insurance plans. However, if a therapy is efficacious and patients are willing to pay out of pocket, clinicians may want to have these options available for their patients.
In an effort to work through these complex issues, a panel of experts was convened at the 47th Annual Scientific Meeting of the Society of Gynecologic Surgeons in Palm Springs, California, on June 29, 2021. This article includes the salient points from that panel discussion.
Fractionated CO2 laser therapy
Fractionated CO2 laser therapy is considered second-line therapy for the treatment of genitourinary syndrome of menopause (GSM). In 2018, the US Food and Drug Administration (FDA) issued a safety warning about the use of CO2 laser therapy and warned patients and clinicians that the FDA had not approved the treatment for vaginal rejuvenation or treatment of vaginal symptoms related to menopause, urinary incontinence, or sexual function. Despite this warning, laser treatments are still performed in many practices.
In 2019, the International Continence Society (ICS) and the International Society for the Study of Vulvovaginal Disease (ISSVD) put out a joint practice consensus statement that essentially did not recommend the routine use of laser treatment for GSM, urinary incontinence, or lichen sclerosus.1 Conversely, the 2020 American Urogynecologic Society (AUGS) published a clinical consensus statement that spoke to the promising results of laser therapy for the treatment of vulvovaginal atrophy, vaginal dryness, and menopausal dyspareunia, with benefits lasting up to 1 year.2 This statement also suggested that the short-term safety profile of the CO2 laser device was favorable.
How CO2 lasers work
Fractionated CO2 laser therapy differs from unfractionated treatment (which often is used in the treatment of condyloma) in that it is not ablative. The laser works by using fractionated beams of light to penetrate the affected tissue to create small wounds in the epithelium and underlying lamina propria, which leads to collagen remodeling and regeneration that then results in the restoration of the superficial epithelium, vaginal rugae, and lubrication.3 Most clinicians perform 3 applications of the laser treatment 6 weeks apart, a recommendation that is based on manufacturer-sponsored studies in menopausal women.
Study results of patient outcomes with laser therapy
GSM. Several retrospective4,5 and prospective studies6-10 have looked at short- and longer-term outcomes in patients undergoing treatment with the CO2 laser. All of these studies showed improvement in patient symptoms related to GSM.
The VeLVET trial, conducted by Paraiso and colleagues, was a randomized trial that compared CO2 laser treatment with vaginal estrogen in women with GSM.11 While the study was underpowered due to cessation of enrollment once the FDA safety warning was issued, the authors reported that at 6 months, both the fractionated CO2 laser therapy group and the vaginal estrogen group had similar improvements, with 70% to 80% of participants reporting satisfaction with treatment. The authors concluded that laser therapy is likely to be as efficacious as vaginal estrogen and may be a good option for patients who cannot use vaginal estrogen to treat GSM.11
Lichen sclerosus. Some data exist on the efficacy of laser therapy for the treatment of lichen sclerosus. One recently published randomized trial showed that at 6 months, fractionated CO2 laser treatment and prior treatment with high potency topical corticosteroids was associated with higher improvement in subjective symptoms and objective measures compared with clobetasol propionate treatment.12 Another trial, however, revealed that laser treatment was not an effective monotherapy treatment for lichen sclerosus when compared with placebo.13 Fewer studies have examined the effect of laser therapy on urinary incontinence.
More prospective data are emerging, evidenced by trials currently registered in ClinicalTrials.gov. While some studies provide evidence that laser therapy may be efficacious in the treatment of vulvovaginal atrophy, additional data are needed to confirm the favorable outcomes observed with laser therapy for the treatment of lichen sclerosus, and a significant amount of data are needed to evaluate the efficacy of laser treatment for urinary incontinence.
Until such evidence is available, fractionated CO2 vaginal laser therapy will remain a fee-for-service treatment option and will be inaccessible to patients who cannot afford the cost of treatment.
Continue to: Hydrogel urethral bulking...
Hydrogel urethral bulking
Urethral bulking agents have been used for 5 decades in the treatment of stress urinary incontinence (SUI) in women. Unlike midurethral slings, in which many medical device companies use the same implant material (microporous, monofilament polypropylene mesh), the material for bulking agents has varied greatly. A 2017 Cochrane review of urethral bulking listed these agents used for this indication: autologous fat, carbon beads, calcium hydroxylapatite, ethylene vinyl alcohol copolymer, glutaraldehyde cross-linked bovine collagen, hyaluronic acid with dextranomer, porcine dermal implant, polytetrafluoroethylene, and silicone particles.14 These agents can be injected through a transurethral or periurethral technique. The review failed to find superiority of one material or injection technique over another.
New bulking agent available
In January 2020, the FDA approved the premarket application for a new bulking agent. This new agent is a permanently implanted, nonresorbable hydrogel that consists of cross-linked polyacrylamide (2.5%) and water (97.5%). It is intended to be used with a transurethral bulking system that includes a rotatable sheath and two 23-guage needles; a total of 1.5 to 2.0 mL of the hydrogel is injected in 3 locations in the proximal urethra per session. Patients may undergo an additional 2 sessions, if needed, at least 4 weeks after the previous session.
Polyacrylamide hydrogel has been used as a bulking agent in cosmetic and ophthalmic surgery for many years, and it was first approved for medical use in Europe in 2001. The initial European data on its use as a urethral bulking agent was published in 2006.15 The first North American data came in 2014 from a multicenter, randomized trial that compared polyacrylamide hydrogel with collagen gel.16 This investigation followed 345 women for 12 months and concluded that the safety and efficacy of polyacrylamide hydrogel was not inferior to collagen, with a little over half of both cohorts demonstrating a 50% or greater decrease in incontinence episodes.
Since these initial studies, 3-year17 and 7-year safety and efficacy data18 have been reported, with reassuring findings, but both studies experienced significant attrition of the original group of patients. The most commonly reported adverse events associated with the procedure are pain at the injection site (4%–14%) and urinary tract infection (3%–7%); transient urinary retention rates range in incidence from 1.5% to 15%.19
Short procedure, long-term results
Given that a urethral bulking procedure can be done in less than 10 minutes in the office under local analgesia, this treatment may lend itself to use in more brittle patient populations. One study of women aged 80 or older showed a greater than 50% decrease in the number of daily pads used for up to 2 years after initial injection.20 Another study found the greatest treatment success in women aged 60 years or older with fewer than 2.5 episodes of SUI per day.21
Platelet-rich plasma therapy
Platelet-rich plasma (PRP) therapy has been used in multiple disciplines for more than 2 decades as a treatment to regenerate damaged tissue, particularly in sports medicine for treating tendonitis as well as in plastic surgery, gynecology, urology, and ophthalmology, and good outcomes have been demonstrated with no serious adverse effects. PRP is a natural product in which high levels of platelets are concentrated through centrifugation with bioactive growth factors, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and insulin growth factor (IGF).22 The activated platelets are then injected autologously back into the patient’s tissue. This process releases activated growth factors that accelerate tissue healing by stimulating the number of reparative cells to create collagen production, angiogenesis, and neurogenesis while fighting infection and downregulating the autoimmune system.
Continue to: Uses for PRP in gynecology...
Uses for PRP in gynecology
In gynecology, dating back to 2007 PRP was shown to facilitate wound healing, when Fanning and colleagues reported PRP applications in gynecologic operative wounds, such as hysterectomies and urogynecologic procedures, to reduce postoperative pain.23 In the last decade, there has been a dramatic increasing trend in the application of PRP injections as an alternative therapy in gynecology to improve intimate health. PRP has been used to treat lichen sclerosus, atrophic vaginitis, SUI, and female sexual dysfunction; however, there is a dearth of studies that compare PRP with traditional therapies.
Runels and colleagues described the effects of localized injections of autologous PRP for the treatment of sexual dysfunction early in 2014.24 Those authors pioneered PRP use in women with dyspareunia and other symptoms related to sexual dysfunction. Women were offered PRP injections into the periurethral area of the Skene glands and the clitoris. Sexual satisfaction and pain were improved but results did not reach statistical significance. The results of this pilot study of 11 patients suggested that PRP injections could perhaps be an effective method to treat certain types of female sexual dysfunction, including desire, arousal, lubrication, and orgasm.
In another pilot study, Long and colleagues looked at the effectiveness of local injection of PRP for treating women with SUI.25 In that study, younger patients with mild severity of SUI had promising results, with up to 75% cured or improved. Results in the older group, with 50% cured or improved, did not reach statistical significance. Other small, limited studies have been conducted under the hypothesis that PRP as an “O-shot” may be a promising treatment that is a safe, effective, nonsurgical, and nonhormonal option for women with dyspareunia from lack of lubrication and related sexual dysfunction, such as decreased libido or arousal.26-29 A pilot study by Behnia-Willison and colleagues demonstrated clinical improvement in PRP use as an alternative to topical steroids for lichen sclerosus.30 Several other studies also have shown efficacy for the treatment of lichen sclerosus.31-34
More evidence of efficacy needed
To date, preliminary studies suggest that PRP holds promise for a host of gynecologic conditions. Since PRP is autologous, there are no significant contraindications, and thus far there have been no known serious adverse effects. However, most health insurers still do not cover this therapy, so for now patients must pay out-of-pocket fees for these treatments.
As we continue to investigate therapies in regenerative medicine, the continued efforts of our discipline are required to conduct well-designed prospective, randomized controlled studies. While initial series suggest that PRP is safe, it is unlikely that this therapy will be embraced widely in the paradigm as an alternative treatment option for many genitourinary symptoms of menopause and vulvar disorders until efficacy is better established.
Radiofrequency therapy
For the past 20 years, radiofrequency (RF) energy has been used through the vagina, urethra, and periurethral tissues for the treatment of genitourinary symptoms, with limited success. More recently, because some patients hesitate to receive mesh implants for treatment of urinary incontinence,35 there has been gravitation to office-based procedures.
In contrast to lasers, which transmit energy through light, RF waves (measured in hertz) transform the kinetic energy of the intracellular atoms, which move and collide, generating thermal energy.36,37 RF therapy has been shown to increase the proportion of smooth muscle and connective tissue; stimulate proliferation of the epithelium, neovascularization, and collagen formation in the lamina propria; and improve natural lubrication.36,38 In addition, RF is:
- ablative when the heat is capable of generating ablation and/or necrosis of the epidermis and dermis
- microablative when energy fractionation produces microscopic columns of ablative thermal lesions in the epidermis and upper dermis, resulting in microscopic columns of treated tissue interspersed with areas of untreated skin,39 and
- nonablative when trauma occurs only in the dermis by heating without causing ablation of the epidermis.39
The RF devices discussed below are used with settings for microablation in the treatment of SUI and sexual health/vaginal laxity, and with nonablative settings in the treatment of GSM.
RF for the treatment of urinary incontinence
Studies with RF have shown its benefits in urinary symptoms as secondary outcomes, such as improvement of SUI.38,40 One theory that favors energy devices as a treatment for SUI is that the treatment strengthens suburethral and pubocervical support, thereby decreasing urethral mobility.41
In 2016, the Viveve system (Viveve) received FDA 510(k) clearance for “use in general surgical procedures for electrocoagulation and hemostasis.” A single-site, randomized, nonblinded pilot study compared 1 treatment (group 1) versus 2 treatments (group 2) with the Viveve system for SUI in 35 participants.42 At 12 months, only for group 2 did mean scores on the Incontinence Impact Questionnaire Short Form (IIQ-7) and the International Consultation on Incontinence Modular Questionnaire-Urinary Incontinence-Short Form (ICIQ-UI-SF) decrease by the minimum clinically important difference of 16 and 2.52 points, respectively, compared with baseline.
The ThermiVa device (ThermiGen, LLC) received FDA clearance for “use in dermatological and general surgical procedures for electrocoagulation and hemostasis” in 2017. A single-site, prospective, double-blind, randomized controlled pilot trial evaluated the efficacy of this device for the treatment of SUI in 20 participants randomly assigned in a 1:1 fashion to active and sham groups.43 At 12 weeks, mean scores of the Urogenital Distress Inventory (UDI-6) and the ICIQ-UI-SF decreased by the minimal clinically important difference only in the treatment group arm. Additionally, 70% of treatment group participants had a negative stress test at 12 weeks compared with 0% of control group participants.43 In another study of 48 patients who were followed longitudinally for 5 months, a substantial improvement in genital appearance was observed.44 Assessment based on validated instruments demonstrated significant improvements in sexual function and SUI.44
A microablative RF device (Wavetronic 6000 Touch Device, Megapulse HF FRAXX system; Loktal Medical Electronics) consists of a vaginal probe with 64 microneedles at the tip, each capable of penetrating to a depth of 1 mm. During activation, delivery of RF energy, which results in vaporization of tissue at 100 °C, occurs in a preset sequence of 8 needles at a time, preventing the overheating of intervening tissue between adjacent needles.
Slongo and colleagues conducted a 3-arm randomized clinical trial that included 117 climacteric women with SUI.45 In group 1, treatment consisted of 3 monthly sessions of RF; group 2 received 12 weekly sessions of pelvic floor muscle training (PFMT); and group 3 received RF treatment plus PFMT simultaneously. Assessments were conducted at baseline and 30 days after the end of therapy using validated questionnaires and scales for urinary, vaginal, and sexual functions, and cytology was used to assess vaginal atrophy. The association between RF and PFMT showed significant improvement in the SUI symptoms assessed by questionnaire. The vaginal symptoms and dryness showed more substantial improvement with the RF treatment, and vaginal laxity showed similar improvement in the 3 treatment groups.45
Continue to: RF for the treatment of GSM...
RF for the treatment of GSM
For women who are not candidates for localized hormone therapy, as well as others who simply do not wish to use hormones, nonablative RF laser therapy may be an alternative for the management of GSM.
The VIVEVE I trial was one of the largest randomized, sham-controlled trials performed to determine the efficacy of vaginal rejuvenation using surface-cooled RF; 174 women received either RF treatment (90 J/cm2) or sham treatment (1 J/cm2).46 Treated participants had a significant improvement in perception of vaginal laxity/looseness and sexual function up to 6 months posttreatment.46 Overall, participants were satisfied with the treatment (77.8%–100%) and reported significant improvements in vaginal laxity and symptoms of atrophy. RF was well tolerated with minimal adverse effects, such as procedure-related erythema and edema of treated tissue, and vaginal discharge. One patient discontinued treatment because of procedural pain.47,48
The ThermiVa system also was evaluated for efficacy in the treatment of GSM in a single-site, double-blind randomized controlled pilot study, the methods of which were previously described above.43 GSM symptoms were evaluated at baseline and 12 weeks using the Vaginal Health Index (VHI) and visual analog scale (VAS). At the 12-week follow-up, compared with baseline scores, VHI scores were unchanged in the control group and improved in the treatment group. Additionally, VAS scores for dyspareunia decreased in the treatment group compared with baseline while VAS for dyspareunia in the sham group did not change from baseline to 12 weeks.
RF treatment for sexual health
The efficacy of the Viveve RF system for female sexual dysfunction was evaluated in an international, randomized, controlled, single-blinded study (n = 154) that compared 6-month outcomes of RF treatment versus sham treatment.46 Although there was a statistically significant improvement in patient-reported sexual dysfunction on validated instruments, it is essential to note that the study was powered for the primary outcome of vaginal laxity. In addition, the study was not adequately powered to evaluate safety; however, the adverse events reported were mild, and the most frequently reported adverse event was vaginal discharge.
Microablative monopolar RF treatment for GSM has been evaluated in 2 single-arm clinical trials that included a total of 70 patients.39,49 Pre- and posttreatment outcomes were analyzed after delivery of 3 treatment sessions 28 to 40 days apart. Although the only significant improvement in quality of life was in the health domain of the World Health Organization Quality of Life Adapted Questionnaire (P = .04), significant improvements in sexual functioning were seen in terms of the desire (P = .002), lubrication (P = .001), satisfaction (P = .003), and pain (P = .007) domains of the Female Sexual Function Index (FSFI) questionnaire except for excitation and orgasm.39 Overall, 100% of participants reported being satisfied or very satisfied with treatments, and 13 of 14 women felt “cured” or “much better.”39 After treatment, significant increases in vaginal Lactobacillus (P<.001), decreases in vaginal pH (P<.001), improvements in maturation of vaginal cellularity (decreased parabasal cells, P<.001; increased superficial cells, P<.001), and increased VHI score (P<.001) alone occurred.49 No adverse events beyond self-limited vaginal burning and redness were reported.39,49 In another study mentioned above, the combination of RF and PFMT in sexual function does not offer benefits superior to those achieved by the therapies alone.45
Evidence on RF treatment does not support marketing efforts
Radiofrequency devices have been marketed for a variety of genitourinary problems in women, with limited high-quality, randomized, comparative evidence of efficacy and durability in the literature. It is unfortunate that RF treatment continues to be promoted by practitioners around the world who cite small, short-term studies that lack biostatistical rigor in their reporting of protocols and results. Statements from both AUGS and the International Urogynecological Association have heeded caution on the use of lasers but they could not even evaluate RF devices due to lack of evidence.2,41
Informed counseling and shared decision making remain the bottom line
By the year 2025, all members of the Baby Boom generation will be aged 60 or older. While in the past there has been a reluctance to discuss women’s sexual health, urinary incontinence, and GSM, the need for open discussion and a variety of treatment options for these conditions has never been more critical.
Many patients prefer office-based therapies over hospital-based procedures, and others are leery of synthetic implants. These concerns are leading toward great interest in the types of treatments covered in this article. However, it is paramount that clinicians are aware of the evidence-based data behind these emerging options so that we can openly and accurately counsel our patients.
As we have shown, the quality of the data behind these officed-based therapies varies significantly. Until a greater body of research data is available, we must carefully balance our desire to meet patient wishes with solid, informed counseling and shared decision making. ●
As more and more gynecologic therapies move to the outpatient setting, keeping up on the latest data regarding emerging options can be challenging. Furthermore, it can be difficult to justify purchasing expensive equipment for the office when a therapy is not covered by medical insurance plans. However, if a therapy is efficacious and patients are willing to pay out of pocket, clinicians may want to have these options available for their patients.
In an effort to work through these complex issues, a panel of experts was convened at the 47th Annual Scientific Meeting of the Society of Gynecologic Surgeons in Palm Springs, California, on June 29, 2021. This article includes the salient points from that panel discussion.
Fractionated CO2 laser therapy
Fractionated CO2 laser therapy is considered second-line therapy for the treatment of genitourinary syndrome of menopause (GSM). In 2018, the US Food and Drug Administration (FDA) issued a safety warning about the use of CO2 laser therapy and warned patients and clinicians that the FDA had not approved the treatment for vaginal rejuvenation or treatment of vaginal symptoms related to menopause, urinary incontinence, or sexual function. Despite this warning, laser treatments are still performed in many practices.
In 2019, the International Continence Society (ICS) and the International Society for the Study of Vulvovaginal Disease (ISSVD) put out a joint practice consensus statement that essentially did not recommend the routine use of laser treatment for GSM, urinary incontinence, or lichen sclerosus.1 Conversely, the 2020 American Urogynecologic Society (AUGS) published a clinical consensus statement that spoke to the promising results of laser therapy for the treatment of vulvovaginal atrophy, vaginal dryness, and menopausal dyspareunia, with benefits lasting up to 1 year.2 This statement also suggested that the short-term safety profile of the CO2 laser device was favorable.
How CO2 lasers work
Fractionated CO2 laser therapy differs from unfractionated treatment (which often is used in the treatment of condyloma) in that it is not ablative. The laser works by using fractionated beams of light to penetrate the affected tissue to create small wounds in the epithelium and underlying lamina propria, which leads to collagen remodeling and regeneration that then results in the restoration of the superficial epithelium, vaginal rugae, and lubrication.3 Most clinicians perform 3 applications of the laser treatment 6 weeks apart, a recommendation that is based on manufacturer-sponsored studies in menopausal women.
Study results of patient outcomes with laser therapy
GSM. Several retrospective4,5 and prospective studies6-10 have looked at short- and longer-term outcomes in patients undergoing treatment with the CO2 laser. All of these studies showed improvement in patient symptoms related to GSM.
The VeLVET trial, conducted by Paraiso and colleagues, was a randomized trial that compared CO2 laser treatment with vaginal estrogen in women with GSM.11 While the study was underpowered due to cessation of enrollment once the FDA safety warning was issued, the authors reported that at 6 months, both the fractionated CO2 laser therapy group and the vaginal estrogen group had similar improvements, with 70% to 80% of participants reporting satisfaction with treatment. The authors concluded that laser therapy is likely to be as efficacious as vaginal estrogen and may be a good option for patients who cannot use vaginal estrogen to treat GSM.11
Lichen sclerosus. Some data exist on the efficacy of laser therapy for the treatment of lichen sclerosus. One recently published randomized trial showed that at 6 months, fractionated CO2 laser treatment and prior treatment with high potency topical corticosteroids was associated with higher improvement in subjective symptoms and objective measures compared with clobetasol propionate treatment.12 Another trial, however, revealed that laser treatment was not an effective monotherapy treatment for lichen sclerosus when compared with placebo.13 Fewer studies have examined the effect of laser therapy on urinary incontinence.
More prospective data are emerging, evidenced by trials currently registered in ClinicalTrials.gov. While some studies provide evidence that laser therapy may be efficacious in the treatment of vulvovaginal atrophy, additional data are needed to confirm the favorable outcomes observed with laser therapy for the treatment of lichen sclerosus, and a significant amount of data are needed to evaluate the efficacy of laser treatment for urinary incontinence.
Until such evidence is available, fractionated CO2 vaginal laser therapy will remain a fee-for-service treatment option and will be inaccessible to patients who cannot afford the cost of treatment.
Continue to: Hydrogel urethral bulking...
Hydrogel urethral bulking
Urethral bulking agents have been used for 5 decades in the treatment of stress urinary incontinence (SUI) in women. Unlike midurethral slings, in which many medical device companies use the same implant material (microporous, monofilament polypropylene mesh), the material for bulking agents has varied greatly. A 2017 Cochrane review of urethral bulking listed these agents used for this indication: autologous fat, carbon beads, calcium hydroxylapatite, ethylene vinyl alcohol copolymer, glutaraldehyde cross-linked bovine collagen, hyaluronic acid with dextranomer, porcine dermal implant, polytetrafluoroethylene, and silicone particles.14 These agents can be injected through a transurethral or periurethral technique. The review failed to find superiority of one material or injection technique over another.
New bulking agent available
In January 2020, the FDA approved the premarket application for a new bulking agent. This new agent is a permanently implanted, nonresorbable hydrogel that consists of cross-linked polyacrylamide (2.5%) and water (97.5%). It is intended to be used with a transurethral bulking system that includes a rotatable sheath and two 23-guage needles; a total of 1.5 to 2.0 mL of the hydrogel is injected in 3 locations in the proximal urethra per session. Patients may undergo an additional 2 sessions, if needed, at least 4 weeks after the previous session.
Polyacrylamide hydrogel has been used as a bulking agent in cosmetic and ophthalmic surgery for many years, and it was first approved for medical use in Europe in 2001. The initial European data on its use as a urethral bulking agent was published in 2006.15 The first North American data came in 2014 from a multicenter, randomized trial that compared polyacrylamide hydrogel with collagen gel.16 This investigation followed 345 women for 12 months and concluded that the safety and efficacy of polyacrylamide hydrogel was not inferior to collagen, with a little over half of both cohorts demonstrating a 50% or greater decrease in incontinence episodes.
Since these initial studies, 3-year17 and 7-year safety and efficacy data18 have been reported, with reassuring findings, but both studies experienced significant attrition of the original group of patients. The most commonly reported adverse events associated with the procedure are pain at the injection site (4%–14%) and urinary tract infection (3%–7%); transient urinary retention rates range in incidence from 1.5% to 15%.19
Short procedure, long-term results
Given that a urethral bulking procedure can be done in less than 10 minutes in the office under local analgesia, this treatment may lend itself to use in more brittle patient populations. One study of women aged 80 or older showed a greater than 50% decrease in the number of daily pads used for up to 2 years after initial injection.20 Another study found the greatest treatment success in women aged 60 years or older with fewer than 2.5 episodes of SUI per day.21
Platelet-rich plasma therapy
Platelet-rich plasma (PRP) therapy has been used in multiple disciplines for more than 2 decades as a treatment to regenerate damaged tissue, particularly in sports medicine for treating tendonitis as well as in plastic surgery, gynecology, urology, and ophthalmology, and good outcomes have been demonstrated with no serious adverse effects. PRP is a natural product in which high levels of platelets are concentrated through centrifugation with bioactive growth factors, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and insulin growth factor (IGF).22 The activated platelets are then injected autologously back into the patient’s tissue. This process releases activated growth factors that accelerate tissue healing by stimulating the number of reparative cells to create collagen production, angiogenesis, and neurogenesis while fighting infection and downregulating the autoimmune system.
Continue to: Uses for PRP in gynecology...
Uses for PRP in gynecology
In gynecology, dating back to 2007 PRP was shown to facilitate wound healing, when Fanning and colleagues reported PRP applications in gynecologic operative wounds, such as hysterectomies and urogynecologic procedures, to reduce postoperative pain.23 In the last decade, there has been a dramatic increasing trend in the application of PRP injections as an alternative therapy in gynecology to improve intimate health. PRP has been used to treat lichen sclerosus, atrophic vaginitis, SUI, and female sexual dysfunction; however, there is a dearth of studies that compare PRP with traditional therapies.
Runels and colleagues described the effects of localized injections of autologous PRP for the treatment of sexual dysfunction early in 2014.24 Those authors pioneered PRP use in women with dyspareunia and other symptoms related to sexual dysfunction. Women were offered PRP injections into the periurethral area of the Skene glands and the clitoris. Sexual satisfaction and pain were improved but results did not reach statistical significance. The results of this pilot study of 11 patients suggested that PRP injections could perhaps be an effective method to treat certain types of female sexual dysfunction, including desire, arousal, lubrication, and orgasm.
In another pilot study, Long and colleagues looked at the effectiveness of local injection of PRP for treating women with SUI.25 In that study, younger patients with mild severity of SUI had promising results, with up to 75% cured or improved. Results in the older group, with 50% cured or improved, did not reach statistical significance. Other small, limited studies have been conducted under the hypothesis that PRP as an “O-shot” may be a promising treatment that is a safe, effective, nonsurgical, and nonhormonal option for women with dyspareunia from lack of lubrication and related sexual dysfunction, such as decreased libido or arousal.26-29 A pilot study by Behnia-Willison and colleagues demonstrated clinical improvement in PRP use as an alternative to topical steroids for lichen sclerosus.30 Several other studies also have shown efficacy for the treatment of lichen sclerosus.31-34
More evidence of efficacy needed
To date, preliminary studies suggest that PRP holds promise for a host of gynecologic conditions. Since PRP is autologous, there are no significant contraindications, and thus far there have been no known serious adverse effects. However, most health insurers still do not cover this therapy, so for now patients must pay out-of-pocket fees for these treatments.
As we continue to investigate therapies in regenerative medicine, the continued efforts of our discipline are required to conduct well-designed prospective, randomized controlled studies. While initial series suggest that PRP is safe, it is unlikely that this therapy will be embraced widely in the paradigm as an alternative treatment option for many genitourinary symptoms of menopause and vulvar disorders until efficacy is better established.
Radiofrequency therapy
For the past 20 years, radiofrequency (RF) energy has been used through the vagina, urethra, and periurethral tissues for the treatment of genitourinary symptoms, with limited success. More recently, because some patients hesitate to receive mesh implants for treatment of urinary incontinence,35 there has been gravitation to office-based procedures.
In contrast to lasers, which transmit energy through light, RF waves (measured in hertz) transform the kinetic energy of the intracellular atoms, which move and collide, generating thermal energy.36,37 RF therapy has been shown to increase the proportion of smooth muscle and connective tissue; stimulate proliferation of the epithelium, neovascularization, and collagen formation in the lamina propria; and improve natural lubrication.36,38 In addition, RF is:
- ablative when the heat is capable of generating ablation and/or necrosis of the epidermis and dermis
- microablative when energy fractionation produces microscopic columns of ablative thermal lesions in the epidermis and upper dermis, resulting in microscopic columns of treated tissue interspersed with areas of untreated skin,39 and
- nonablative when trauma occurs only in the dermis by heating without causing ablation of the epidermis.39
The RF devices discussed below are used with settings for microablation in the treatment of SUI and sexual health/vaginal laxity, and with nonablative settings in the treatment of GSM.
RF for the treatment of urinary incontinence
Studies with RF have shown its benefits in urinary symptoms as secondary outcomes, such as improvement of SUI.38,40 One theory that favors energy devices as a treatment for SUI is that the treatment strengthens suburethral and pubocervical support, thereby decreasing urethral mobility.41
In 2016, the Viveve system (Viveve) received FDA 510(k) clearance for “use in general surgical procedures for electrocoagulation and hemostasis.” A single-site, randomized, nonblinded pilot study compared 1 treatment (group 1) versus 2 treatments (group 2) with the Viveve system for SUI in 35 participants.42 At 12 months, only for group 2 did mean scores on the Incontinence Impact Questionnaire Short Form (IIQ-7) and the International Consultation on Incontinence Modular Questionnaire-Urinary Incontinence-Short Form (ICIQ-UI-SF) decrease by the minimum clinically important difference of 16 and 2.52 points, respectively, compared with baseline.
The ThermiVa device (ThermiGen, LLC) received FDA clearance for “use in dermatological and general surgical procedures for electrocoagulation and hemostasis” in 2017. A single-site, prospective, double-blind, randomized controlled pilot trial evaluated the efficacy of this device for the treatment of SUI in 20 participants randomly assigned in a 1:1 fashion to active and sham groups.43 At 12 weeks, mean scores of the Urogenital Distress Inventory (UDI-6) and the ICIQ-UI-SF decreased by the minimal clinically important difference only in the treatment group arm. Additionally, 70% of treatment group participants had a negative stress test at 12 weeks compared with 0% of control group participants.43 In another study of 48 patients who were followed longitudinally for 5 months, a substantial improvement in genital appearance was observed.44 Assessment based on validated instruments demonstrated significant improvements in sexual function and SUI.44
A microablative RF device (Wavetronic 6000 Touch Device, Megapulse HF FRAXX system; Loktal Medical Electronics) consists of a vaginal probe with 64 microneedles at the tip, each capable of penetrating to a depth of 1 mm. During activation, delivery of RF energy, which results in vaporization of tissue at 100 °C, occurs in a preset sequence of 8 needles at a time, preventing the overheating of intervening tissue between adjacent needles.
Slongo and colleagues conducted a 3-arm randomized clinical trial that included 117 climacteric women with SUI.45 In group 1, treatment consisted of 3 monthly sessions of RF; group 2 received 12 weekly sessions of pelvic floor muscle training (PFMT); and group 3 received RF treatment plus PFMT simultaneously. Assessments were conducted at baseline and 30 days after the end of therapy using validated questionnaires and scales for urinary, vaginal, and sexual functions, and cytology was used to assess vaginal atrophy. The association between RF and PFMT showed significant improvement in the SUI symptoms assessed by questionnaire. The vaginal symptoms and dryness showed more substantial improvement with the RF treatment, and vaginal laxity showed similar improvement in the 3 treatment groups.45
Continue to: RF for the treatment of GSM...
RF for the treatment of GSM
For women who are not candidates for localized hormone therapy, as well as others who simply do not wish to use hormones, nonablative RF laser therapy may be an alternative for the management of GSM.
The VIVEVE I trial was one of the largest randomized, sham-controlled trials performed to determine the efficacy of vaginal rejuvenation using surface-cooled RF; 174 women received either RF treatment (90 J/cm2) or sham treatment (1 J/cm2).46 Treated participants had a significant improvement in perception of vaginal laxity/looseness and sexual function up to 6 months posttreatment.46 Overall, participants were satisfied with the treatment (77.8%–100%) and reported significant improvements in vaginal laxity and symptoms of atrophy. RF was well tolerated with minimal adverse effects, such as procedure-related erythema and edema of treated tissue, and vaginal discharge. One patient discontinued treatment because of procedural pain.47,48
The ThermiVa system also was evaluated for efficacy in the treatment of GSM in a single-site, double-blind randomized controlled pilot study, the methods of which were previously described above.43 GSM symptoms were evaluated at baseline and 12 weeks using the Vaginal Health Index (VHI) and visual analog scale (VAS). At the 12-week follow-up, compared with baseline scores, VHI scores were unchanged in the control group and improved in the treatment group. Additionally, VAS scores for dyspareunia decreased in the treatment group compared with baseline while VAS for dyspareunia in the sham group did not change from baseline to 12 weeks.
RF treatment for sexual health
The efficacy of the Viveve RF system for female sexual dysfunction was evaluated in an international, randomized, controlled, single-blinded study (n = 154) that compared 6-month outcomes of RF treatment versus sham treatment.46 Although there was a statistically significant improvement in patient-reported sexual dysfunction on validated instruments, it is essential to note that the study was powered for the primary outcome of vaginal laxity. In addition, the study was not adequately powered to evaluate safety; however, the adverse events reported were mild, and the most frequently reported adverse event was vaginal discharge.
Microablative monopolar RF treatment for GSM has been evaluated in 2 single-arm clinical trials that included a total of 70 patients.39,49 Pre- and posttreatment outcomes were analyzed after delivery of 3 treatment sessions 28 to 40 days apart. Although the only significant improvement in quality of life was in the health domain of the World Health Organization Quality of Life Adapted Questionnaire (P = .04), significant improvements in sexual functioning were seen in terms of the desire (P = .002), lubrication (P = .001), satisfaction (P = .003), and pain (P = .007) domains of the Female Sexual Function Index (FSFI) questionnaire except for excitation and orgasm.39 Overall, 100% of participants reported being satisfied or very satisfied with treatments, and 13 of 14 women felt “cured” or “much better.”39 After treatment, significant increases in vaginal Lactobacillus (P<.001), decreases in vaginal pH (P<.001), improvements in maturation of vaginal cellularity (decreased parabasal cells, P<.001; increased superficial cells, P<.001), and increased VHI score (P<.001) alone occurred.49 No adverse events beyond self-limited vaginal burning and redness were reported.39,49 In another study mentioned above, the combination of RF and PFMT in sexual function does not offer benefits superior to those achieved by the therapies alone.45
Evidence on RF treatment does not support marketing efforts
Radiofrequency devices have been marketed for a variety of genitourinary problems in women, with limited high-quality, randomized, comparative evidence of efficacy and durability in the literature. It is unfortunate that RF treatment continues to be promoted by practitioners around the world who cite small, short-term studies that lack biostatistical rigor in their reporting of protocols and results. Statements from both AUGS and the International Urogynecological Association have heeded caution on the use of lasers but they could not even evaluate RF devices due to lack of evidence.2,41
Informed counseling and shared decision making remain the bottom line
By the year 2025, all members of the Baby Boom generation will be aged 60 or older. While in the past there has been a reluctance to discuss women’s sexual health, urinary incontinence, and GSM, the need for open discussion and a variety of treatment options for these conditions has never been more critical.
Many patients prefer office-based therapies over hospital-based procedures, and others are leery of synthetic implants. These concerns are leading toward great interest in the types of treatments covered in this article. However, it is paramount that clinicians are aware of the evidence-based data behind these emerging options so that we can openly and accurately counsel our patients.
As we have shown, the quality of the data behind these officed-based therapies varies significantly. Until a greater body of research data is available, we must carefully balance our desire to meet patient wishes with solid, informed counseling and shared decision making. ●
- Preti M, Viera-Baptista P, Digesu GA, et al. The clinical role of LASER for vulvar and vaginal treatments in gynecology and female urology: an ICS/ISSVD best practice consensus document. J Lower Genital Tract Dis. 2019;23:151-160.
- Alshiek J, Garcia B, Minassian V, et al. Vaginal energy-based devices: AUGS clinical consensus statement. Female Pelvic Med Reconstr Surg. 2020;26:287-298.
- Streicher LF. Vulvar and vaginal fractional CO2 laser treatments for genitourinary syndrome of menopause: NAMS practice pearl. Menopause. 2018;25:571-573.
- Gardner AN, Aschkenazi SO. The short-term efficacy and safety of fractional CO2 laser therapy for vulvovaginal symptoms in menopause, breast cancer, and lichen sclerosus. Menopause. 2021; 28:511-516.
- Balchander D, Nyirjesy P. Fractionated CO2 laser therapy in recalcitrant lichen sclerosus. J Lower Genital Tract Disease. 2020;24:225-228.
- Pieralli A, Fallani MG, Becorpi A, et al. Fractional CO2 laser for vulvovaginal atrophy (VVA) dyspareunia relief in breast cancer survivors. Arch Gynecol Obstet. 2016;294:841-846.
- Pieralli A, Bianchi C, Longinotti M, et al. Long-term reliability of fractionated CO2 laser as a treatment of vulvovaginal atrophy (VVA) symptoms. Arch Gynecol Obstet. 2017; 296:973-978.
- Sokol ER, Karram MM. Use of novel fractional CO2 laser for the treatment of genitourinary syndrome of menopause: 1-year outcomes. Menopause. 2017;24: 810-814.
- Pagano T, Conforti A, Buonfantino C, et al. Effect of rescue fractional microablative CO2 laser on symptoms and sexual dysfunction in women affected by vulvar lichen sclerosus resistant to long-term use of topic corticosteroid: a prospective longitudinal study. Menopause. 2020;27:418-422.
- Sindou-Faurie T, Louis-Vahdat C, Oueld Es Cheikh E, et al. Evaluation of the efficacy of fractional CO2 laser in the treatment of vulvar and vaginal menopausal symptoms. Arch Gynecol Obstet. 2021;303:955-963.
- Paraiso MFR, Ferrando CA, Sokol ER, at al. A randomized clinical trial comparing vaginal laser therapy to vaginal estrogen therapy in women with genitourinary syndrome of menopause: the VeLVET trial. Menopause. 2019;27:50-56.
- Burkett LS, Siddique M, Zeymo A, et al. Clobetasol compared with fractionated carbon dioxide laser for lichen sclerosus: a randomized controlled trial. Obstet Gynecol. 2021;137:968-978.
- Mitchell L, Goldstein AT, Heller D, et al. Fractionated carbon dioxide laser for the treatment of vulvar lichen sclerosus: a randomized controlled trial. Obstet Gynecol. 2021;136:979-987.
- Kirchin V, Page T, Keegan PE, et al. Urethral injection therapy for urinary incontinence in women. Cochrane Database Syst Rev. 2017;7:CD003881.
- Lose G, Mouritsen L, Nielson JB. A new bulking agent (polyacrylamide hydrogel) for treating stress urinary incontinence in women. BJU Int. 2006;98:100-104.
- Sokol ER, Karram MM, Dmochowski R. Efficacy and safety of polyacrylamide hydrogel for the treatment of female stress incontinence: a randomized, prospective, multicenter North American study. J Urol. 2014;192:843-849.
- Pai A, Al-Singary W. Durability, safety and efficacy of polyacrylamide hydrogel (Bulkamid) in the management of stress and mixed urinary incontinence: three year follow up outcomes. Cent European J Urol. 2015;68:428-433.
- Brosche T, Kuhn A, Lobodasch K, et al. Seven-year efficacy and safety outcomes of Bulkamid for the treatment of stress urinary incontinence. Neurourol Urodyn. 2021;40:502-508.
- Kasi AD, Pergialiotis V, Perrea DN, et al. Polyacrylamide hydrogel (Bulkamid) for stress urinary incontinence in women: a systematic review of the literature. Int Urogynecol J. 2016;27:367-375.
- Vecchioli-Scaldazza CV, Smaali C, Morosetti C, et al. Polyacrylamide hydrogel (Bulkamid) in female patients of 80 or more years with urinary incontinence. Int Braz J Urol. 2014;40:37-43.
- Elmelund M, Sokol ER, Darram MM, et al. Patient characteristics that may influence the effect of urethral injection therapy for female stress urinary incontinence. J Urol. 2019;202:125-131.
- Sanoulis V, Nikolettos N, Vlahos N. The use of platelet-rich plasma in the gynecological clinical setting: a review. HJOG. 2019;18:55-65.
- Fanning J, Murrain L, Flora R, et al. Phase I/II prospective trial of autologous platelet tissue graft in gynecologic surgery. J Minim Invasive Gynecol. 2007;14:633-637.
- Runels CE, Melnick H, DeBourbon E, et al. A pilot study of the effect of localized injections of autologous platelet rich plasma (PRP) for the treatment of female sexual dysfunction. J Womens Health Care. 2014;3:4.
- Long CY, Lin KL, Shen CR, et al. A pilot study: effectiveness of local injection of autologous platelet-rich plasma in treating women with stress urinary incontinence. Sci Rep. 2021;11:1584.
- Matz EJ, Pearlman AM, Terlecki RP. Safety and feasibility of platelet rich fibrin matrix injections for treatment of common urologic conditions. Investig Clin Urol. 2018;59:61-65.
- Neto JB. O-Shot: platelets rich plasma in intimate female treatment. J Womens Health Care. 2017;6:5.
- Nikolopoulos KI, Pergialiotis V, Perrea D, et al. Restoration of the pubourethral ligament with platelet rich plasma for the treatment of stress urinary incontinence. Med Hypotheses. 2016;90:29-31.
- Hersant B, SidAhmed-Mezi M, Belkacemi Y, et al. Efficacy of injecting platelet concentrate combined with hyaluronic acid for the treatment of vulvovaginal atrophy in postmenopausal women with a history of breast cancer: a phase 2 pilot study. Menopause. 2018;25:1124-1130.
- Behnia-Willison F, Pour NR, Mohamadi B, et al. Use of platelet-rich plasma for vulvovaginal autoimmune conditions like lichen sclerosus. Plast Reconstr Surg Glob Open. 2016;4:e1124.
- Goldstein AT, King M, Runels C, et al. Intradermal injection of autologous platelet-rich plasma for the treatment of vulvar lichen sclerosus. J Am Acad Dermatol. 2017;76:158-160.
- Casabona F, Priano V, Vallerino V, et al. New surgical approach to lichen sclerosus of the vulva: the role of adipose-derived mesenchymal cells and platelet-rich plasma in tissue regeneration. Plast Reconstr Surg. 2010;126:210e-211e.
- Franic D, Iternica Z, Franic-Ivanisevic M. Platelet-rich plasma (PRP) for the treatment of vulvar lichen sclerosus in a premenopausal woman: a case report. Case Rep Womens Health. 2018;18: e0062.
- Posey LK, Runels C. In office surgery and use of platelet rich plasma for the treatment of vulvar lichen sclerosus to alleviate painful sexual intercourse. J Lower Genital Tract Dis. 2017;21(4S):S14.
- Stachowicz AM, Hoover ML, Karram MM. Clinical utility of radiofrequency energy for female genitourinary dysfunction: past, present, and future. Int Urogynecol J. 2021;32:1345-1350.
- Tadir Y, Gaspar A, Lev-Sagie A, et al. Light and energy based therapeutics for genitourinary syndrome of menopause: consensus and controversies. Lasers Surg Med. 2017;49:137-159.
- US Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, MD, on efforts to safeguard women’s health from deceptive health claims and significant risks related to devices marketed for use in medical procedures for “vaginal rejuvenation.” https://www.fda.gov/news-events/pressannouncements/statement-fda-commissioner-scott-gottlieb-mdefforts-safeguard-womens-health-deceptive-health-claims. Updated August 2, 2018. Accessed August 13, 2021.
- Vicariotto F, Raichi M. Technological evolution in the radiofrequency treatment of vaginal laxity and menopausal vulvo-vaginal atrophy and other genitourinary symptoms: first experiences with a novel dynamic quadripolar device. Minerva Ginecol. 2016;68:225-236.
- Kamilos MF, Borrelli CL. New therapeutic option in genitourinary syndrome of menopause: pilot study using microablative fractional radiofrequency. Einstein (Sao Paulo). 2017;15:445-551.
- Caruth JC. Evaluation of the safety and efficacy of a novel radiofrequency device for vaginal treatment. Surg Technol Int. 2018;32:145-149.
- Shobeiri SA, Kerkhof MH, Minassian VA, et al. IUGA committee opinion: laser-based vaginal devices for treatment of stress urinary incontinence, genitourinary syndrome of menopause, and vaginal laxity. Int Urogynecol J. 2019;30:371-376.
- Allan BB, Bell S, Husarek K. Early feasibility study to evaluate the Viveve system for female stress urinary incontinence: interim 6-month report. J Womens Health (Larchmt). 2020;29:383-389.
- Leibaschoff G, Izasa PG, Cardona JL, et al. Transcutaneous temperature controlled radiofrequency (TTCRF) for the treatment of menopausal vaginal/genitourinary symptoms. Surg Technol Int. 2016;29:149-159.
- Desai SA, Vakil Z, Kroumpouzos G. Transcutaneous temperature-controlled radiofrequency treatment: improvement in female genital appearance, sexual dysfunction, and stress urinary incontinence. Aesthet Surg J. 2021;sjab174. doi: 10.1093/asj/sjab174.
- Slongo H, Lunardi AL, Riccetto CL, et al. Microablative radiofrequency versus pelvic floor muscle training for stress urinary incontinence: a randomized controlled trial. Int Urogynecol J. 2021. doi: 10.1007 /s00192-021-04758-2.
- Krychman M, Rowan CG, Allan BB, et al. Effect of single-treatment, surface-cooled radiofrequency therapy on vaginal laxity and female sexual function: the VIVEVE I randomized controlled trial. J Sex Med. 2017;14:215-225.
- Zerbinati N, Serati M, Origoni M, et al. Microscopic and ultrastructural modifications of postmenopausal atrophic vaginal mucosa after fractional carbon dioxide laser treatment. Lasers Med Sci. 2015;30: 429-436.
- Juhasz ML, Korta DZ, Mesinkovska NA. Vaginal rejuvenation: a retrospective review of lasers and radiofrequency devices. Dermatol Surg. 2021;47:489-494.
- Sarmento AC, Fernandes FS, Marconi C, et al. Impact of microablative fractional radiofrequency on the vaginal health, microbiota, and cellularity of postmenopausal women. Clinics (Sao Paulo). 2020;75:e1750.
- Preti M, Viera-Baptista P, Digesu GA, et al. The clinical role of LASER for vulvar and vaginal treatments in gynecology and female urology: an ICS/ISSVD best practice consensus document. J Lower Genital Tract Dis. 2019;23:151-160.
- Alshiek J, Garcia B, Minassian V, et al. Vaginal energy-based devices: AUGS clinical consensus statement. Female Pelvic Med Reconstr Surg. 2020;26:287-298.
- Streicher LF. Vulvar and vaginal fractional CO2 laser treatments for genitourinary syndrome of menopause: NAMS practice pearl. Menopause. 2018;25:571-573.
- Gardner AN, Aschkenazi SO. The short-term efficacy and safety of fractional CO2 laser therapy for vulvovaginal symptoms in menopause, breast cancer, and lichen sclerosus. Menopause. 2021; 28:511-516.
- Balchander D, Nyirjesy P. Fractionated CO2 laser therapy in recalcitrant lichen sclerosus. J Lower Genital Tract Disease. 2020;24:225-228.
- Pieralli A, Fallani MG, Becorpi A, et al. Fractional CO2 laser for vulvovaginal atrophy (VVA) dyspareunia relief in breast cancer survivors. Arch Gynecol Obstet. 2016;294:841-846.
- Pieralli A, Bianchi C, Longinotti M, et al. Long-term reliability of fractionated CO2 laser as a treatment of vulvovaginal atrophy (VVA) symptoms. Arch Gynecol Obstet. 2017; 296:973-978.
- Sokol ER, Karram MM. Use of novel fractional CO2 laser for the treatment of genitourinary syndrome of menopause: 1-year outcomes. Menopause. 2017;24: 810-814.
- Pagano T, Conforti A, Buonfantino C, et al. Effect of rescue fractional microablative CO2 laser on symptoms and sexual dysfunction in women affected by vulvar lichen sclerosus resistant to long-term use of topic corticosteroid: a prospective longitudinal study. Menopause. 2020;27:418-422.
- Sindou-Faurie T, Louis-Vahdat C, Oueld Es Cheikh E, et al. Evaluation of the efficacy of fractional CO2 laser in the treatment of vulvar and vaginal menopausal symptoms. Arch Gynecol Obstet. 2021;303:955-963.
- Paraiso MFR, Ferrando CA, Sokol ER, at al. A randomized clinical trial comparing vaginal laser therapy to vaginal estrogen therapy in women with genitourinary syndrome of menopause: the VeLVET trial. Menopause. 2019;27:50-56.
- Burkett LS, Siddique M, Zeymo A, et al. Clobetasol compared with fractionated carbon dioxide laser for lichen sclerosus: a randomized controlled trial. Obstet Gynecol. 2021;137:968-978.
- Mitchell L, Goldstein AT, Heller D, et al. Fractionated carbon dioxide laser for the treatment of vulvar lichen sclerosus: a randomized controlled trial. Obstet Gynecol. 2021;136:979-987.
- Kirchin V, Page T, Keegan PE, et al. Urethral injection therapy for urinary incontinence in women. Cochrane Database Syst Rev. 2017;7:CD003881.
- Lose G, Mouritsen L, Nielson JB. A new bulking agent (polyacrylamide hydrogel) for treating stress urinary incontinence in women. BJU Int. 2006;98:100-104.
- Sokol ER, Karram MM, Dmochowski R. Efficacy and safety of polyacrylamide hydrogel for the treatment of female stress incontinence: a randomized, prospective, multicenter North American study. J Urol. 2014;192:843-849.
- Pai A, Al-Singary W. Durability, safety and efficacy of polyacrylamide hydrogel (Bulkamid) in the management of stress and mixed urinary incontinence: three year follow up outcomes. Cent European J Urol. 2015;68:428-433.
- Brosche T, Kuhn A, Lobodasch K, et al. Seven-year efficacy and safety outcomes of Bulkamid for the treatment of stress urinary incontinence. Neurourol Urodyn. 2021;40:502-508.
- Kasi AD, Pergialiotis V, Perrea DN, et al. Polyacrylamide hydrogel (Bulkamid) for stress urinary incontinence in women: a systematic review of the literature. Int Urogynecol J. 2016;27:367-375.
- Vecchioli-Scaldazza CV, Smaali C, Morosetti C, et al. Polyacrylamide hydrogel (Bulkamid) in female patients of 80 or more years with urinary incontinence. Int Braz J Urol. 2014;40:37-43.
- Elmelund M, Sokol ER, Darram MM, et al. Patient characteristics that may influence the effect of urethral injection therapy for female stress urinary incontinence. J Urol. 2019;202:125-131.
- Sanoulis V, Nikolettos N, Vlahos N. The use of platelet-rich plasma in the gynecological clinical setting: a review. HJOG. 2019;18:55-65.
- Fanning J, Murrain L, Flora R, et al. Phase I/II prospective trial of autologous platelet tissue graft in gynecologic surgery. J Minim Invasive Gynecol. 2007;14:633-637.
- Runels CE, Melnick H, DeBourbon E, et al. A pilot study of the effect of localized injections of autologous platelet rich plasma (PRP) for the treatment of female sexual dysfunction. J Womens Health Care. 2014;3:4.
- Long CY, Lin KL, Shen CR, et al. A pilot study: effectiveness of local injection of autologous platelet-rich plasma in treating women with stress urinary incontinence. Sci Rep. 2021;11:1584.
- Matz EJ, Pearlman AM, Terlecki RP. Safety and feasibility of platelet rich fibrin matrix injections for treatment of common urologic conditions. Investig Clin Urol. 2018;59:61-65.
- Neto JB. O-Shot: platelets rich plasma in intimate female treatment. J Womens Health Care. 2017;6:5.
- Nikolopoulos KI, Pergialiotis V, Perrea D, et al. Restoration of the pubourethral ligament with platelet rich plasma for the treatment of stress urinary incontinence. Med Hypotheses. 2016;90:29-31.
- Hersant B, SidAhmed-Mezi M, Belkacemi Y, et al. Efficacy of injecting platelet concentrate combined with hyaluronic acid for the treatment of vulvovaginal atrophy in postmenopausal women with a history of breast cancer: a phase 2 pilot study. Menopause. 2018;25:1124-1130.
- Behnia-Willison F, Pour NR, Mohamadi B, et al. Use of platelet-rich plasma for vulvovaginal autoimmune conditions like lichen sclerosus. Plast Reconstr Surg Glob Open. 2016;4:e1124.
- Goldstein AT, King M, Runels C, et al. Intradermal injection of autologous platelet-rich plasma for the treatment of vulvar lichen sclerosus. J Am Acad Dermatol. 2017;76:158-160.
- Casabona F, Priano V, Vallerino V, et al. New surgical approach to lichen sclerosus of the vulva: the role of adipose-derived mesenchymal cells and platelet-rich plasma in tissue regeneration. Plast Reconstr Surg. 2010;126:210e-211e.
- Franic D, Iternica Z, Franic-Ivanisevic M. Platelet-rich plasma (PRP) for the treatment of vulvar lichen sclerosus in a premenopausal woman: a case report. Case Rep Womens Health. 2018;18: e0062.
- Posey LK, Runels C. In office surgery and use of platelet rich plasma for the treatment of vulvar lichen sclerosus to alleviate painful sexual intercourse. J Lower Genital Tract Dis. 2017;21(4S):S14.
- Stachowicz AM, Hoover ML, Karram MM. Clinical utility of radiofrequency energy for female genitourinary dysfunction: past, present, and future. Int Urogynecol J. 2021;32:1345-1350.
- Tadir Y, Gaspar A, Lev-Sagie A, et al. Light and energy based therapeutics for genitourinary syndrome of menopause: consensus and controversies. Lasers Surg Med. 2017;49:137-159.
- US Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, MD, on efforts to safeguard women’s health from deceptive health claims and significant risks related to devices marketed for use in medical procedures for “vaginal rejuvenation.” https://www.fda.gov/news-events/pressannouncements/statement-fda-commissioner-scott-gottlieb-mdefforts-safeguard-womens-health-deceptive-health-claims. Updated August 2, 2018. Accessed August 13, 2021.
- Vicariotto F, Raichi M. Technological evolution in the radiofrequency treatment of vaginal laxity and menopausal vulvo-vaginal atrophy and other genitourinary symptoms: first experiences with a novel dynamic quadripolar device. Minerva Ginecol. 2016;68:225-236.
- Kamilos MF, Borrelli CL. New therapeutic option in genitourinary syndrome of menopause: pilot study using microablative fractional radiofrequency. Einstein (Sao Paulo). 2017;15:445-551.
- Caruth JC. Evaluation of the safety and efficacy of a novel radiofrequency device for vaginal treatment. Surg Technol Int. 2018;32:145-149.
- Shobeiri SA, Kerkhof MH, Minassian VA, et al. IUGA committee opinion: laser-based vaginal devices for treatment of stress urinary incontinence, genitourinary syndrome of menopause, and vaginal laxity. Int Urogynecol J. 2019;30:371-376.
- Allan BB, Bell S, Husarek K. Early feasibility study to evaluate the Viveve system for female stress urinary incontinence: interim 6-month report. J Womens Health (Larchmt). 2020;29:383-389.
- Leibaschoff G, Izasa PG, Cardona JL, et al. Transcutaneous temperature controlled radiofrequency (TTCRF) for the treatment of menopausal vaginal/genitourinary symptoms. Surg Technol Int. 2016;29:149-159.
- Desai SA, Vakil Z, Kroumpouzos G. Transcutaneous temperature-controlled radiofrequency treatment: improvement in female genital appearance, sexual dysfunction, and stress urinary incontinence. Aesthet Surg J. 2021;sjab174. doi: 10.1093/asj/sjab174.
- Slongo H, Lunardi AL, Riccetto CL, et al. Microablative radiofrequency versus pelvic floor muscle training for stress urinary incontinence: a randomized controlled trial. Int Urogynecol J. 2021. doi: 10.1007 /s00192-021-04758-2.
- Krychman M, Rowan CG, Allan BB, et al. Effect of single-treatment, surface-cooled radiofrequency therapy on vaginal laxity and female sexual function: the VIVEVE I randomized controlled trial. J Sex Med. 2017;14:215-225.
- Zerbinati N, Serati M, Origoni M, et al. Microscopic and ultrastructural modifications of postmenopausal atrophic vaginal mucosa after fractional carbon dioxide laser treatment. Lasers Med Sci. 2015;30: 429-436.
- Juhasz ML, Korta DZ, Mesinkovska NA. Vaginal rejuvenation: a retrospective review of lasers and radiofrequency devices. Dermatol Surg. 2021;47:489-494.
- Sarmento AC, Fernandes FS, Marconi C, et al. Impact of microablative fractional radiofrequency on the vaginal health, microbiota, and cellularity of postmenopausal women. Clinics (Sao Paulo). 2020;75:e1750.