Effectiveness of alternative GSM therapies: "twist of fate" or natural evolution?

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Abstract

The study and development of new therapies for genitourinary syndrome of menopause (GSM) remain an area of focus in modern gynecology. The relevance and need for scientific research in this area are undeniable due to the significant negative impact of GSM on patients' quality of life. At this point, however, a great deal of controversy is arising as the knowledge of the treatment of GSM-associated disorders deepens. Local hormonal therapy remains the "gold standard" for vulvovaginal atrophy treatment, but alternative therapies for GSM are launching in the pharmaceutical market. Have we got more answers? Yes. Have we got more questions? Sure. So why does the very fact of studying GMS require us to be so pedantic and focus the attention of the entire global medical community? Let's get to the bottom of this.

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The prevalence of HUMS in postmenopausal women exceeds 50%, and according to some data, 80% of postmenopausal women have at least one symptom of HUMS [1–3]. Many patients and some doctors treat VVA as a natural aging process, underestimate the danger of this condition, and do not receive/do not prescribe treatment [4–6]. According to the results of a survey of physicians, 62% of them talk about VVA with postmenopausal patients, but only 7–10% actively initiate such a conversation [7]. Without therapy, the symptoms of HUMS inevitably progress, but a critically small proportion of patients receive treatment. However, even when prescribing therapy, less than half of the patients adhere to the prescribed regimen [7, 8]. For example, Kingsberg SA et al. found that only 7% of women aged 45–90 years (mean age 58 years, n=1858) receive the prescribed treatment with VVAs (local estrogens or systemic selective estrogen receptor modulators) [8].
The problem within the problem is the management of patients with breast cancer (BC): in this group of patients, genital atrophy not only worsens the quality of life, but is also an additional side effect of adjuvant therapy [9, 10]. In patients with breast cancer, genital symptoms are more pronounced, appear at a younger age, which further reduces the quality of life [9].
Given the existing limitations in HUMS therapy, it is necessary to offer alternative methods of treatment to those women who have contraindications to the use of hormonal agents or refuse them.

We searched the scientific literature in the PubMed, CochraneLibrary, Science Direct, ELibrary databases for the keywords CO2-laser/CO2-laser, Er:YAG-laser/erbium laser, vulvovaginal atrophy/vulvovaginal atrophy, genitourinary syndrome of menopause , treatment / treatment, postmenopausal age / postmenopausal age for 2012-2022.
Laser devices transmit or create thermal energy in tissues, causing a controlled, locus-limited temperature increase to 45–50°C, a supraphysiological level sufficient to initiate a “heat shock reaction” (HSR; Heat shock reaction). Under the influence of HSR, cellular metabolism changes and overexpression of specific “heat shock proteins” (HSP; Heat shock proteins) occurs. These changes are temporary. It should be noted that the synthesis of heat shock proteins increases under many types of stress exposure: they are always present in tissues in a small amount (about 2%), but under the influence of stress factors (for example, during thermal exposure), their proportion increases to 20% [11, 12].
Under experimental conditions, it has been demonstrated that HSPs (for example, HSP70 or HSP47, whose production actively increases after laser exposure) can enhance the expression of a number of cytokines, growth factors, and other bioactive substances. For example, an increase in HSP synthesis increases the expression of transforming growth factor (TGF)-beta, which is considered a key stimulator of fibroblast formation. The latter directly produce collagen and extracellular matrix [11, 12]. HSPs actively bind to denatured proteins and maintain them in a state capable of subsequent recovery [12]. One of the heat shock proteins required for the early stages of collagen biosynthesis, HSP47, can bind to monomeric proteins and induce their assembly into higher-order assemblies, which are characterized by increased stability compared to monomeric peptide structures [12, 13]. These processes occurring at the ultrastructural level underlie the therapeutic effect of laser devices in the treatment of women with HUMS.

Currently, laser therapy is widely used in medicine, mainly in dermatology for the treatment of skin lesions, removal of hypertrophic and keloid scars, for skin resurfacing and remodeling in patients with age-related changes [11]. In gynecology, a fractional microablative CO2 laser and a non-ablative photothermal erbium laser (Er:YAG) are used to treat HUMS. The fractional CO2 laser was introduced to the medical community in 2014. Histologically controlled studies conducted in subsequent years (Salvatore S et al., 2015; Zerbinati N et al., 2014) confirmed its effectiveness in vulvovaginal tissue remodeling and symptom reduction in patients with VVA [14, 15].
The first publication on the therapeutic possibilities of the erbium laser is dated 2015 [16]. Vizintin Z et al. described a non-invasive thermal energy technology that stimulates connective tissue remodeling and neocollagenesis by hyperthermia of vaginal wall collagen. Clinically, this is expressed by an increase in the density and elasticity of the vaginal tissues, a decrease in VVA symptoms [16].
Both lasers are used according to the same indications in order to enhance regenerative processes in tissues. However, they differ in their mechanism of action on tissues. Under the influence of the energy of the erbium laser, the vaginal tissue (“below” the surface epithelium) is heated to a supraphysiological temperature without overheating the outer layer. Such a temperature regime stimulates the contraction of collagen fibers and neocollagenesis, and the process of formation of new fibers continues after the end of the laser procedure. As a result of collagen remodeling and neocollagenesis, the density and elasticity of the vaginal tissue increase [16, 17]. The action of a carbon dioxide-based microablative fractional laser is associated with the formation of thermal energy during the evaporation of water in the cells of the lamina propria of the vaginal mucosa [18]. In this case, the microablative effect occurs pointwise, which also excludes damage to the surface epithelium. Among the histological and clinical results of carbon dioxide laser therapy, stimulation of neocollagenesis and neovascularization processes, swelling of the basic substance of the connective tissue of the vaginal wall, a decrease in vaginal pH, an increase in the moisture content of the vaginal mucosa, and an improvement in blood flow were confirmed [19].

The formation of new collagen, the restoration of its structure, neovascularization and the production of the main matrix can help reduce vaginal laxity; restoration of hydration and a decrease in vaginal pH improves the protective properties of the mucous membrane and "strengthens" the barrier to genital infection. All these tissue changes represent the process of healing the vaginal wall, which also manifests itself at the ultrastructural level [14].
To assess the effectiveness of therapy, the dynamics of patient complaints, the results of gynecological examination and pH-metry, as well as data from filling out special questionnaires are analyzed: the visual analogue scale (VAS) of VVA symptoms, the vaginal health index (VHI) and the female sexual function index (FSFI) [17, 20–22].
• On a 10-point VAS scale, patients note the severity of VVA symptoms.
• The FSFI six-block questionnaire includes questions about libido, subjective arousal, lubrication, orgasm, satisfaction, and pain during intercourse. This questionnaire is designed to assess the severity of dyspareunia and general sexual disorders.
• The VHI scale is designed to analyze five elements: pH of the vaginal environment, mucosal secretion and integrity of the epithelium of the vaginal membrane, its elasticity and tissue hydration (from 5 to 25 points). If the sum of the points obtained is less than 15, then they speak of atrophic vaginitis.

Also, to evaluate the results of therapy, the vaginal maturation index (VMI) is used, which is determined by a cytological examination of a vaginal smear: the proportions of superficial, intermediate, and parabasal cells are estimated. The decrease in the proportion of parabasal cells indicates a positive trend.
Since 2014–2015, several dozens of clinical and experimental observations on the efficacy and safety of laser therapy have been completed. Not all of them correspond to a high degree of evidence, but the results are interesting for intermediate conclusions and planning of future studies [23–32]. The studied treatment protocol includes three laser procedures, but in one of the works, the authors evaluated the therapeutic effect when using two additional sessions [30].
According to a randomized study by Politano CA et al. (n=72), of the three types of treatment (CO2 laser therapy; local estrogen therapy; lubricant) after 14 weeks, the best results according to the VHI and FSFI questionnaires were obtained in the laser treatment and hormone therapy groups [23]. The authors noted an increase in elasticity, vaginal moisture, and a decrease in pH. However, VHI scores were higher after laser therapy than after estrogen and lubrication (18.68 versus 15.11 and 10.44, respectively). After treatment with a CO2 laser, an improvement in the histological picture was also noted - a decrease in the number of basal cells, an increase in the number of superficial ones. According to the authors' conclusions, fractionated CO2 laser therapy leads to better short-term effects in the treatment of HUMS than topical estrogens or lubricants. Paraiso MFR et al. obtained similar results after carbon laser treatment and local estrogen therapy [24].

LiJ et al. compared the efficacy and safety of fractional CO2 laser and topical estrogen therapy for HUMS symptoms [25] and found no significant difference between the groups. The severity of HUMS symptoms (burning in the vagina, dryness, and dyspareunia) was assessed using VHI and VAS at the beginning of treatment, 1, 3, 6, and 12 months after therapy. In the laser therapy group, there were significant differences in VHI after the first or second treatment session, as well as 1, 3, 6, and 12 months after CO2 laser therapy compared with the pre-treatment value. In the group of local estrogen therapy, similar results were obtained, while no significant side effects were observed in both groups [25]. Aguiar LB et al. found better results in terms of relief of dysuric disorders (urinary incontinence, overactive bladder) after fractional CO2 laser therapy compared with local estrogen therapy (1.3 times) [26].
In almost all studies, a decrease in VVA symptoms was noted when assessing vaginal dryness, burning, itching, and dyspareunia on the VAS scale, an increase in total scores on the VHI and FSFI scales, and acidification of the vaginal environment, which confirm the effectiveness of laser therapy [17, 27]. The VMI score also shows a significant improvement in both cytology and symptoms [28-31].
A number of studies have confirmed clinical improvement after treatment with a carbon laser, which persists after 12 months [18], 18 months [27], and 24 months of follow-up [32]. One of the works showed the preservation of positive results of therapy after 36 months [33]. The confirmed duration of the clinical effect after the use of an erbium laser is shorter: subjective and objective assessments return to the initial (before treatment) level after 18–24 months [34].

Rosner-Tenerowicz A et al. in a prospective open-label study (n=205), confirmed that positive changes after the use of CO₂ remodeling microablative laser therapy in relation to dyspareunia, vaginal dryness and burning sensation, vaginal laxity, and urinary incontinence persist 12 months after treatment [35].
Alexiades MR evaluated the results of CO2 laser treatment at 1, 3, 6, and 12 months [36] using VHI, FSFI, pH-metry, and examination results. epithelial integrity and moisture. The author noted a statistically significant improvement as a result of therapy compared with baseline at all stages of observation (up to 12 months). The mean total VHI score increased by 93.2% after 6 months and by 81.4% after 12 months compared to baseline. Mean FSFI scores after 12 months increased from baseline by 46.9%. A normal/near-normal VHI at 3.6 and 12 months post-treatment was achieved in 88%, 88%, and 63% of patients with a menopause duration of less than 3 years and in 30%, 40%, and 10% of patients with a postmenopausal duration of more than 3 years. Patient satisfaction after was 94% at follow-up for 12 months. Safety analysis showed no discomfort in most patients; of mild side effects, temporary erythema and edema were noted, cases of serious side effects associated with treatment were not registered.
Adabi K et al. assessed the effect of a fractional CO2 laser on the quality of life and symptoms of HUMS using health questionnaires (SF-12), FSFI, VHI, and the International Urinary Incontinence Consultation Questionnaire (ICIQ) [37]. After treatment, the quality of life improved significantly in terms of somatic, sexual, social functions and mental health. The frequency of dysuric disorders significantly decreased, the condition of the vaginal epithelium improved.Eder SE evaluated the results of VVA CO2 laser treatment immediately after treatment, 3, 6 months [38], and 12, 15, and 18 months after the last machine therapy session [34]. The mean VHI score improved significantly (13.89±4.25 vs. 11.93±3.82 before treatment; p<0.05) 1 month after the first laser treatment, 3 and 6 months after the end of the intervention (16.43 ±4.20 and 17.46±4.07, respectively). Almost all VVA symptoms improved significantly after the first of three laser treatments. The FSFI increased significantly (22.36±10.40 vs. 13.78±7.70 before treatment) and remained significantly higher than baseline at follow-up visits at 3 and 6 months [38]. The mean VHI after 12, 15 and 18 months remained elevated compared to baseline (12.4±4.0), respectively 16.3±4.5, 16.9±4.6 and 17.1±4, 6. Almost all VVA symptoms improved significantly 12 months after the end of treatment, and positive changes persisted at 15 and 18 months. At the 12-month visit, the total FSFI score increased significantly at 12 months (24.4±6.9) and remained high at 15 and 18 months (22.2±6.7, 25.8±6.6 vs baseline 13 .78±7.70) [34].
Interestingly, placebo-controlled trials comparing laser therapy with sham intervention have reported improvements in symptoms in both groups, suggesting a possible placebo contribution [39-41]. Cruff J et al. noted a comparable clinical improvement in VAS, VHI, and FSFI scales after laser therapy and after placebo, with no difference between groups [42]. Similarly to Li FG et al., the results of HUMS treatment with fractional carbon laser after 12 months did not differ from placebo [43].
In the treatment of HUMS in patients with breast cancer or at high risk of breast cancer, laser therapy is a promising alternative therapy that allows to achieve an adequate clinical response without resorting to hormonal therapy. Becorpi A et al. in the treatment of VVA in patients with breast cancer, changes in the patterns of inflammatory and modulatory cytokines, minor changes in the vaginal microbiome, pronounced remodeling of the vaginal epithelium after carbon laser procedures were found [44].A number of clinical observations [45, 46] have shown that laser therapy reduces the symptoms of VVA in women with breast cancer (FSFI, VHI and VAS indices increase), while no side effects were recorded in the short-term follow-up period. However, there are no safety data for breast cancer recurrence from these studies, and serum estradiol levels were not measured in any of them.
The longest observation (18 months) of the results of erbium laser treatment of patients with breast cancer and VVA was carried out by Gambacciani et al [46]. Symptoms were assessed using the VAS and VHI indices before treatment, after 1, 3, 6, 12 and 18 months.
• VAS vaginal dryness was 4.4±1.2 cm after the 3rd procedure and 5.5±1.5 cm after 12 months (initial value 8.5±1.0 cm).
• VAS dyspareunia decreased from baseline 7.5±1.5 cm to 4.2±0.9 cm after the 3rd treatment and to 5.1±1.8 cm 12 months after the last laser treatment. After 18 months, this figure was 6.5±1.8 cm.
• The total VHI score after three procedures was 21.0±1.4, 12 months after the last laser application — 18±1.8; after 18 months — 14.8±1 (before treatment — 8.1±1.3).
No adverse events were recorded during the study [43].
Veron L analyzed the results of CO2 laser treatment of a similar cohort of patients and obtained similar results [27]. The effectiveness of laser therapy was assessed before treatment, 6 and 18 months after, using the FSFI index, the Ditrovie scale, and vaginal pH [27]. A Pap smear was also performed and the nature of the maturation of the epithelium was noted. Paired statistical tests were used to compare outcomes between baseline, 6 months, and 18 months. The pH level of the vaginal environment slightly decreased, the nature of maturation in the Pap smear did not change, and there was a significant improvement in the quality of sexual life after 6 and 18 months. The side effects were very mild.According to the authors' conclusions, erbium and CO2 laser therapy is effective for the treatment of HUMS in women treated for breast cancer. Information about the low safety profile of laser therapy in the treatment of this cohort of patients in these studies has not been received [27, 46].
Of the adverse events during laser procedures, a slight burning sensation and pain were recorded directly during the procedure, however, as genital atrophy decreased, the severity of side effects decreased [30, 45, 47, 48].conclusions
1. VVA is of serious medical and socioeconomic importance, affecting more than 50% of postmenopausal women. The frequency of VVA will increase in the future due to the aging of the population and the increase in the number of women in the postmenopausal period.
2. HUMS is a chronic progressive disease, the symptoms of which, if left untreated, worsen and significantly reduce the quality of life. Symptoms of HUMS affect the social and sexual life of patients.
3. Despite the high prevalence of HUMS, a critically small number of patients receive treatment. Currently, local hormone therapy with estrogen has a proven effect on VVA. However, there are objective and subjective difficulties with its prescription: women do not receive recommendations because doctors underestimate the clinical problem of VVA, refuse treatment or have contraindications to it.
4. According to the findings of many researchers, CO₂ microablative laser treatment can be effective in reducing the symptoms of vulvovaginal atrophy such as vaginal laxity, dryness, pain during intercourse, burning, as well as reduce the severity of stress urinary incontinence and urge incontinence symptoms. Positive changes persist for 12 months or more after the end of therapy.5. A number of studies have shown the efficacy and safety of laser therapy in the treatment of BC patients with VVA, who are contraindicated in traditional hormonal treatment with local estrogen preparations.
6. Laser treatment of VVA using carbon or erbium units is a promising, minimally invasive, yet effective therapeutic strategy for the relief of symptoms of VVA with proven safety in the short term, but the efficacy and safety of laser technologies in the treatment of HUMS require further study in studies of high quality.

 

 

 

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About the authors

Mekan R. Orazov

People’s Friendship University of Russia (RUDN University)

Author for correspondence.
Email: omekan@mail.ru
ORCID iD: 0000-0002-5342-8129

D. Sci. (Med.)

Russian Federation, Moscow

Viktor E. Radzinsky

People’s Friendship University of Russia (RUDN University)

Email: radzinsky@mail.ru
ORCID iD: 0000-0003-4956-0466

D. Sci. (Med.), Prof., Corr. Memb. RAS

Russian Federation, Moscow

Evgeny D. Dolgov

People’s Friendship University of Russia (RUDN University)

Email: 1586dolgde@gmail.com
ORCID iD: 0000-0001-6709-5209

Clinical Resident

Russian Federation, Moscow

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1. Fig. 1. Estriol synthesis route.

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