Therapeutic Choices for Genitourinary Syndrome of Menopause (GSM) in Breast Cancer Survivors: A Systematic Review and Update

(1) Background: Genitourinary syndrome of menopause (GSM) is a medical condition that can affect breast cancer survivors (BCS). This is a complication that often can occur as a result of breast cancer treatment, causing symptoms such as vaginal dryness, itching, burning, dyspareunia, dysuria, pain, discomfort, and impairment of sexual function. BCS who experience these symptoms negatively impact multiple aspects of their quality of life to the point that some of them fail to complete adjuvant hormonal treatment; (2) Methods: In this systematic review of the literature, we have analyzed possible pharmacological and non-pharmacological treatments for GSM in BCS. We reviewed systemic hormone therapy, local hormone treatment with estrogens and androgens, the use of vaginal moisturizers and lubricants, ospemifene, and physical therapies such as radiofrequency, electroporation, and vaginal laser; (3) Results: The data available to date demonstrate that the aforementioned treatments are effective for the therapy of GSM and, in particular, vulvovaginal atrophy in BCS. Where possible, combination therapy often appears more useful than using a single line of treatment; (4) Conclusions: We analyzed the efficacy and safety data of each of these options for the treatment of GSM in BCS, emphasizing how often larger clinical trials with longer follow-ups are needed.


Introduction
Breast cancer represents a global issue in public health, ranking as the first most diagnosed cancer in women and the second most common cause of cancer-related death after lung and bronchial cancer [1].
According to data from GLOBOCAN 2020 provided by the International Agency for Research on Cancer (IARC), the incidence is growing worldwide with an estimated number of 2.261.419 new cases per year, while average mortality is constantly decreasing, On the other hand, young women with a positive pathogenic mutation for BRCA 1 and 2 who agree to undergo preventive bilateral salpingo-oophorectomy will inevitably develop an early surgically induced menopause and a form of secondary permanent amenorrhea.
We are talking about a severe clinical condition that causes a reduction in the quality of life of such patients, so it is important to diagnose and treat it.
Unfortunately, this issue is often underestimated and undertreated, due to a lack of knowledge by health care specialists or due to a fear of BC recurrence and poor familiarity with the various available options. In fact, a study conducted in 2021 by Pearson et al., aiming to improve the understanding of health professionals' knowledge and management of genitourinary symptoms in women with early breast cancer, by administering a survey to 144 oncology health professionals, demonstrated that most respondents recognized it as a common problem, but only 16% felt confident managing these symptoms and prescribing adequate therapies [14].
A similar study on 120 breast oncologists was conducted in 2017 by Biglia's group in Turin: they assessed that, despite the fact that none of the physicians considered VVA a transient event or a secondary problem in BCS, only half of the oncologists (48%) directly illustrated VVA to the patients as a possible consequence. 41% of the oncologists referred BCSs to gynecologists to define VVA treatment, while 35.1% managed it alone [15].
Therefore, we aim to underline the importance of treating this condition in order to enhance BCS's overall care and quality of life.
According to today's knowledge, we have several therapy options: • Hormonal, systemic, and topical treatments; • Non-hormonal topical treatments; • Physical therapy.
The gold standard for this pathology would be the use of estrogen, which is however contraindicated in women with BCS; in fact, the treatment is still the subject of discussion in this population.
According to current guidelines [16], first-line treatment is a non-hormonal therapy, such as moisturizing and lubricating vaginal creams, which appear to be useful in treating vaginal dryness and lead to an improvement in symptoms. If there is no response, local hormonal treatments are carried out: low-dose intravaginal ovules or intravaginal cream based on testosterone or DHEA. However, the problem is represented by estrogen-based creams and vaginal rings in subjects receiving aromatase inhibitor therapy because systemic absorption has also been demonstrated [16].
The revolution in this area is represented by physical therapies such as electroporation and radiofrequency with the possibility of conveying different active ingredients inside the tissues or even by laser therapy, which allows for improved tropism of the vulvovaginal mucosa.
The objective of this systematic review of the literature is to analyze the various types of treatment currently present with regard to GSM in BCS and understand how to combine them in the best way.

Materials and Methods
A systematic review of the literature on SGM management and therapeutic options in BCS was conducted on PubMed, Medline, and the Cochrane Library using the following search terms: genitourinary syndrome of menopause (GSM); breast cancer survivors (BCS); menopause; vulvovaginal atrophy (VVA); aromatase inhibitors (AI); vaginal lubricants; vaginal moisturizers; local hormone therapy; vaginal laser therapy.
Using PRISMA guidelines [17] for systematic review, we initially identified through database searches 648 records; after duplicates were removed, the records were 633; 577 of them were excluded based on the title and the abstract, so we assessed 76 full-text articles for eligibility. Full text excluded because it did not meet the review criteria was 47. Finally, we included in our systematic review 38 studies, all in English (Figure 1). count. The North American Menopause Society (NAMS) https://www.menopause.org (accessed on 24 February 2023); https://www.asco.org (accessed on 24 February 2023), the American Society of Clinical Oncology (ASCO); the International Menopause Society (IMS) https://www.imsociety.org (accessed on 24 February 2023); the Canadian Menopause Society https://www.sigmamenopause.com (accessed on 24 February 2023); the European Menopause and Andropause Society (EMAS) https://www.emas-online.org (accessed on 24 February 2023); the International Society for the Study of Women's Sexual Health (ISSWSH) https://www.isswsh.org (accessed on 24 February 2023).
Using PRISMA guidelines [17] for systematic review, we initially identified through database searches 648 records; after duplicates were removed, the records were 633; 577 of them were excluded based on the title and the abstract, so we assessed 76 full-text articles for eligibility. Full text excluded because it did not meet the review criteria was 47. Finally, we included in our systematic review 38 studies, all in English (Figure 1).

Discussion
The first-line treatment for vulvovaginal atrophy as well as for BCS is represented by non-hormonal therapies [18]. The group of non-hormonal therapies includes numerous categories of drugs and others that can play an optimal role in the treatment of pain during the sexual act and in general for vaginal well-being. Regarding GSM non-hormonal treatments in BCS, we have: Moisturizers and lubricants: the role of vaginal moisturizers is to maintain the integrity and elasticity of the vagina; these are products that must be used regularly, therefore independently of sexual activity. Lubricants, on the other hand, are useful in reducing the sensation of discomfort during sexual acts. As far as lubricants are concerned, the WHO recommends using lubricants that have the following characteristics: osmolarity lower than 1200 mOsm/kg; this is because higher values are toxic and irritating to the vaginal mucosa. Glycerol content in the lubricant <9.9% mass fraction; propylene <8.3% mass fraction; if a glycol mixture is used, the limit must be less than 8.3% of the mass balance. The product must also be free from parabens, chlorhexidine, and polyquaternary compounds [19].
Hyaluronic acid (HA): linear polymer with large dimensions; it is flexible and extremely polar. It is a compound that we find to be the main component of the extracellular matrix (ECM), together with collagen, elastin, and fibronectin. It is one of the main constituents of the connective tissue of humans and mammals [20]. In the last 20 years, several studies have been carried out aimed at understanding the role of HA in both physiological and pathological conditions, and the biological mechanisms that regulate its synthesis, degradation, and metabolic activities have been analyzed. HA is synthesized on the inner surface of the plasma membrane and then extruded extracellularly; the synthesis is mediated by hyaluronic acid synthetase (HAS); we have 3 types of this enzyme with different functions: HAS1 and 2 polymerize HA of similar length, and HAS3 synthesizes HA with a short chain [21]. Long-chain HA has been shown to promote cell quiescence and only superficially support cellular integrity; low-molecular-weight HA instead promotes tissue repair. Taking into account what has been said, low molecular weight HA finds application both in the gynecological and urological fields. Several studies have shown that the topical use of ovules containing low molecular weight hyaluronic acid (LMW-HA) is a valid alternative in the short-and long-term treatment of problems such as itching, burning, dyspareunia, and dryness, symptoms therefore caused by alterations in the vaginal mucosa resulting both from treatments such as laser therapy, cryotherapy, and radiotherapy and from a lack of estrogen and therefore a GSM [22].
Polynucleotides: they are a mixture of low-molecular-weight fractions that form a linear polymer of deoxyribonucleotides joined by phosphodiester bonds. These are molecules capable of activating fibroblasts by activating purinergic receptors; they also stimulate growth by acting on CD39 receptors [23].
Phytoestrogens: they are substances of vegetable nature that are non-steroids, able to bind to estrogen receptors but with a weaker effect, from 100 to 1000 times a day. They also have antioxidant, anti-inflammatory, and antihypertensive properties. In the phytoestrogen family, isoflavones are of particular interest in the treatment of menopause, in particular genistein, contained in soy. Although the information and studies available are still very few, it has been seen that this molecule could be useful in the management of menopause problems both in the short and long term and therefore could also find utility in the treatment of GSM in BCS women [24].
Vasodilators: the extractive pyranocoumarin is a molecule with a vasodilating action. It interacts with the type 1 calcium channels at the level of the smooth muscles, causing an increase in the local flow. It has been observed that the local administration of a spray based on visnadine 10 minutes before sexual intercourse has a positive effect, so it is also a candidate among the non-hormonal alternatives to be used in the treatment of GSM in BCS [25].
Vaginal vitamin D and E: a study was conducted to understand the effect of vaginal suppositories based on vitamin E and D on vaginal atrophy in BCS. It is a randomized controlled trial. The result was an improvement in vaginal atrophy by administering these vaginal suppositories every night for 8 weeks [26].
Vaginal/oral probiotics: the vaginal microbiota (in detail, Lactobacillus spp.) plays a very important role in the health of the lower genitourinary tract, and a decrease has been observed during menopause. It has been observed that postmenopausal women with a vaginal microbiota dominated by Gardnerella vaginalis and low Lactobacillus develop vaginal atrophy much more easily than postmenopausal women with a microbiota high in Lactobacillus [27]. The administration of probiotics orally or vaginally is still the subject of a strong debate today, but on the basis of what they report, it certainly finds its usefulness.
Platelet-rich plasma: although there are few studies in the literature to date, it has been deduced that the use of platelet-rich plasma in the treatment of GSM, both as a single treatment and as an adjuvant, appears to be promising and has a good safety profile [28].
Mechanical (dilators and sexual activity): the use of dilators has been shown to support and help women suffering from genital pelvic pain and penetration disorders, which can be present in women with GSM [29].
The main problem with these substances, however, is that they are not able to regenerate the vaginal barriers or improve their characteristics. They can only slow down the evolution of the pathological picture, and the improvements obtained tend to be lost quickly after suspension. These are generally creaming moisturizers or lubricating gels composed mainly of water, vegetable oils, or silicone derivatives [30].
The main advantages related to non-hormonal therapy instead are represented by having practically no side effects; consequently, they can be used for long periods of time without the need for suspension periods. On the other hand, long periods are necessary for these treatments to start to take effect.
All non-hormonal therapies used in GSM therapy for breast cancer patients are summarized in Table 1.
From an etiopathogenic point of view, we know that the cause of vaginal atrophy, even in BCS patients, is caused by a drop in estrogen levels; consequently, a therapeutic treatment based on hormonal supplementation would seem logical. Local estrogen administration has been shown to be the most effective method. The effect consists of an improvement in the tropism of the vaginal mucous membranes and in tissue regeneration with the formation of new vessels and an increase in cell layers with the restoration of adequate local flora and an adequate pH [31].
The methods of administration of estrogens are numerous; there are solutions in cream, vaginal rings, ovules, or gels. The estrogen that is most frequently used in the treatment of vaginal atrophy is estriol.
Conversely, other recent prospective studies have suggested that the use of vaginal estrogen therapy may increase serum estrogen levels, resulting in a possible increased risk of BC recurrence. Santen et al. reported that an increase in serum estradiol levels produced by vaginal estrogens may not exceed the normal range of postmenopausal serum estradiol [32]. Some works in the literature suggest the use of estriol instead of estradiol for BCS since its metabolic clearance is faster. Estriol is not FDA-approved for any indication and should be used as an off-label hormone option [33]. Surely other studies are needed to validate the safety of hormone therapy with clear certainty, considering that the vaginal walls are extremely vascularized and that the use of local therapy does not exclude with certainty the entry into the circulation of hormones. Surely, from our point of view, we would like to specify that a case-by-case evaluation is necessary. Oil-in-water emulsion during 28 days.

Subjective
Symptoms; safety and tolerability.

--
The difference in symptom frequency before-after the treatment was significant (p < 0.0001).
This treatment seems to improve VVA symptoms with a short treatment.
Pharmaceuticals 2023, 16  The administration of HRT should be limited to topical use; in fact, international guidelines do not recommend systemic administration [34].
Promestriene (3-propyl ethyl, 17β-methyl estradiol) is a synthetic estrogen analog with minimal systemic absorption for the topical treatment of vaginal atrophy, which can be used in BCF patients due to its poor activity on the breast. Studies by mass spectrometry have confirmed the low systemic activity even after months of therapeutic doses in women with high-grade estrogen receptor-positive breast tumors [35]. However, in vitro studies concluded that the potential estrogen-like properties of promestriene to stimulate the growth of estrogen receptor-reactive breast cancer cell lines, especially under conditions of estrogen deprivation, suggest caution when prescribing for vaginal atrophy in postmenopausal BCS. Its ability to activate growth and gene expression in ER-BC cells deserves further study.
Women who underwent surgery for luminal early breast cancer are all candidates to receive endocrine adjuvant systemic treatment, which was clearly related to a significant improvement both in progression-free survival (PFS) and overall survival (OS) [36,37].
In ER and PgR-positive BC, estrogens induce the proliferation of tumor cells and support the progression of the disease. Hormone therapy is administered in order to decrease the levels of circulating estrogens by using drugs active on the hypothalamicpituitary-ovarian axis and the estrogen receptors [38,39].
Mechanisms and sites of synthesis of sexual hormones change over a woman's life depending on reproductive age. In pre-menopausal women, estrogens are mainly produced by the granulosa cells of the ovary, whereas in post-menopausal women, the primary mechanism of production is the peripheral aromatization of C19-steroids by aromatase located in the adipose tissue [40].
Based upon these biological assumptions, pre-and post-menopausal women are candidates to receive different treatment options.
Two randomized trials, TEXT and SOFT, demonstrated that the use of LHRH-analogues (e.g., triptorelin, goserelin, and leuprorelin) in association with tamoxifen or exemestane resulted in a significant survival benefit for premenopausal women [41].
The ATAC and BIG 1-98 trials showed that in post-menopausal patients, monotherapy with aromatase inhibitors (e.g., anastrozole, letrozole) yielded better outcomes when compared with tamoxifen. In this group, the use of LHRH analogs is not recommended because ovarian production of estrogens is supposed to be physiologically abolished [42,43].
About 95% of patients exposed to endocrine therapy experience at least one druginduced adverse event (AE), among whom 25-30% reach grade 3 or 4. The early discontinuation rate because of AEs is approximately 20%. Most common AEs include increased cardiovascular and thromboembolic risk, osteoporosis, and those issues that come under the name of genitourinary syndrome of menopause (GSM) [41].
Systemic loss of estrogen results in physiological and structural modifications within the genital structures and vaginal mucosa. Changes include reduced cervical gland secretions, deterioration of tissue, a decrease in blood flow, loss of elasticity, thinning of tissue and epithelium, and an increased pH. These changes are responsible for vaginal dryness and irritation, dyspareunia, decreased libido, frequent urinary tract infections, and urinary incontinence, which together are known as vulvovaginal atrophy or GSM [44,45].
All these symptoms have a great impact on quality of life and need to be properly recognized and managed by the treating physicians, often requiring a multidisciplinary approach. For a long time, this condition has gone undiagnosed and untreated due to a lack of awareness and the paucity of evidence about a safe and effective therapy. From an analysis of the literature and from daily clinical practice, it emerged that there is a lot of difficulty on the part of doctors in administering hormone replacement therapy in patients with previous breast cancer, due to the possible repercussions and side effects. The main fears are related to the risk of interfering with adjuvant therapy, thus favoring any relapses. Numerous works in the literature explain how the risk of tumor reactivation or recurrence is very low [46].
Currently, the cornerstone of treatment for GSM in patients receiving antiestrogen therapy is non-hormonal products. These kinds of solutions are not able to reverse atrophy once it has occurred but can help alleviate symptoms by increasing vaginal moisture, thus avoiding the use of any hormone-based compounds [47].
When non-hormonal products fail to control symptoms, estrogen-based therapy is the only effective option available.
The detrimental effect of systemic estrogen administration was established by two randomized trials. The HABITS trial enrolled 434 patients taking AIs with GSM and randomly assigned them to receive hormone therapy (estradiol hemihydrate and norethisterone) for 2 years or the best symptomatic treatment [48]. The Stockholm trial randomized 378 patients with the same characteristics to receive estradiol and medroxyprogesterone acetate or non-HT. Both studies demonstrated that systemic expositions to estrogens are associated with a significantly increased risk of recurrence of breast cancer (HR 3.5) or new primary development, thus contraindicating the use of this strategy in breast cancer survivors [49].
Although the role of systemic HT is well known, the debate about the safety of its administration is still open. When asked, 71% of oncologists mentioned that the main reason not to prescribe vaginal estrogens is the concern about the potential systemic absorption and the consequent possibility of increased risk of recurrence [15].
Dew et al., in a small cohort study, and Le Ray et al., in a case-control study, of 340 patients with early BC, investigated the BC recurrence risk associated with the use of vaginal estrogen therapy [50,51]. In both works, there is no evidence of an increased risk of recurrence.
In a Danish observational study, a cohort of postmenopausal women with earlystage invasive estrogen receptor-positive nonmetastatic BC who received no treatment or 5 years of adjuvant endocrine therapy were followed over time to evaluate the recurrence and mortality that each had and according to VET, MHT, or no therapy received. The authors concluded that in postmenopausal BCS, neither VET nor MHT was associated with an increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors [52].
However, the studies had several limitations, including a small sample size and a short follow-up.
Therefore, it remains unclear whether VET or MHT is safe for women treated for BC [53,54].
Among women without a history of BC, a meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer reported an increased risk of primary BC among women treated with MHT compared with never-users, whereas VET was not associated with an increased risk of BC [55,56].
When discussing circulating estrogen levels, it is important to highlight that there is no validated safe threshold, but it is commonly assumed that post-menopausal levels must be achieved. There is not a shared opinion about what specific estradiol or estrone levels should raise concern for breast cancer survivors. In postmenopausal women not receiving hormone therapy, average estradiol levels reach 14.1 pg/mL and estrone levels 27.5 pg/mL; it is unclear if keeping values within the typical postmenopausal range is sufficient to decrease the risk of BC recurrence [57].
Estradiol systemic absorption is dose-dependent, and it is influenced by dose, formulation, and positioning in the vagina. During the last few years, several clinical trials were designed to analyze the pharmacokinetics of different vaginal devices to assess safety and efficacy [58].
Eugster-Hausmann et al. conducted a study in which 58 postmenopausal women received 10 mg or 25 mg estradiol vaginal tablets. The trial proved that systemic estradiol absorption with the 10 mg tablet was lower when compared with the 25 mg tablet. Furthermore, after 1 year of treatment with the 10 mg vaginal tablet, levels of estrogen in the body were within the menopausal range (2.44 to 12.08 pg/mL), indicating minimal absorption and a potentially safe alternative in breast cancer survivors receiving AIs [59].
Other treatments that have been considered include intravaginal androgens, based on the concept that administration may act on androgen receptors that have been identified in the wall of the vagina. Local administration of testosterone at the vaginal level appeared to trigger the activation of estrogen and androgen receptors in the vaginal epithelial layers without activating estrogen receptors in other tissues due to the lack of aromatase at this level. Testosterone can induce proliferation of the vaginal epithelium, but the conversion of testosterone to estrogen is blocked by Ais, and thus, it may be effective in reversing the atrophic changes without increasing circulating estrogen levels and compromising aromatase inhibitor therapy [60].
Some recent studies are evaluating the effects of a new androgen, dehydroepiandrosterone (DHEA), in the treatment of vaginal dryness in patients with previous BC [61]. Labrie et al. (2017) in their randomized clinical trial demonstrated the efficacy of prasterone (administered intravaginally at 0.50% 6.5 mg) in postmenopausal women suffering from moderate to severe dyspareunia due to vulvovaginal atrophy. In particular, an average 35.1% decrease over placebo in the percentage of parabasal cells (p < 0.0001), an average 7.7% increase in the percentage of superficial cells (p < 0.0001), and a mean 0.72 pH unit decrease in vaginal pH (p < 0.0001) were observed. Moreover, a very positive evaluation was obtained on the acceptability of the technique of administration of the insert, whereas the male partners reported a very positive evaluation of the changes observed in their sexual partners [62].
At present, this androgen appears to be the only one approved by the FDA for the treatment of GSM in the form of prasterone, the synthetic analog of DHEA.
Barton et al. conducted a phase III randomized clinical trial that evaluated vaginal administration of DHEA at the doses of 3.25 or 6.5 mg compared with plain moisturizer in postmenopausal women with a history of breast (97%) or gynecologic cancer who could be receiving HT (56%). Peripheral blood sample analysis showed that circulating estradiol was significantly increased in those receiving 6.5 mg/d DHEA but not in those receiving 3.25 mg/d DHEA or AI therapy. In both arms, mean estradiol concentrations remained lower than 5 pg/mL. Assuming that hormone concentrations, even though slightly increased, remain in the lowest half or quartile of the postmenopausal range, the FDA has approved vaginal DHEA for the treatment of GSM [63]. However, the prasterone technical data sheet includes a warning against its use in BCS.
There are no studies directly comparing vaginal DHEA to vaginal estrogens in terms of efficacy or studies comparing systemic hormone levels; therefore, there can be no recommendation for one over the other in BCS. Vaginal testosterone cream and an estradiolreleasing vaginal ring also proved to safely improve GSM symptoms in BCS. A study by Witherby et al. supported the safety of vaginal testosterone at the dose of 150 mg or 300 mg daily for treating vulvovaginal atrophy in patients with breast cancer receiving AI therapy, not detecting any significant elevation in serum estradiol levels (<8 pg/mL) at either dose of testosterone [64].
Melisko et al. conducted a randomized phase II trial evaluating the safety and efficacy of intravaginal testosterone cream or a vaginal ring for 12 weeks in postmenopausal women receiving AIs who had symptoms of vulvovaginal atrophy. The intervention was considered unsafe if more than 25% of patients had elevations in serum estradiol greater than 10 pg/mL and at least 10 pg/mL above baseline after treatment initiation. Both interventions met the primary safety end point and improved vaginal atrophy, sexual interest, and dysfunction [65].
In conclusion, according to the American College of Obstetricians and Gynecologists (ACOG) recommendations, the first-line approach to managing GSM in BCS receiving HT is non-hormonal options, but when refractory or severe symptoms occur, the use of vaginal estradiol or DHEA can be considered a safe option to be offered to patients to improve their quality of life [54,57].
Novel emerging approaches, including SERMs, TSECs, estriol, and neurokinin Binhibitors, showed promising activity in managing GSM symptoms with a hypothetical neutral activity on BC. Further investigations in women affected by BC are required to assess the safety and efficacy of these compounds [66].
Another emerging therapy for the treatment of VVA is the vaginal laser. The first studies were performed using a CO 2 fractional laser approved by the Food and Drug Administration (FDA) as a therapy for GSM [67]. The mechanism of action of the laser consists in stimulating progressive neo-collagenases and fibroblast activation with the production of new trabecular-type collagen. The active fibroblasts in the lamina propria also determine an increase in elastin. The use of reverse transcriptase with PCR allowed to demonstrate of a significant increase of pro-collagen mRNA and interleukin-b and TGF-b1, with epithelial reactivation and cellular differentiation [68].
Subsequently, the Erbium laser was introduced, which is better at promoting vascularization of the vaginal mucosa due to a direct correlation between energy density and penetration depth. In fact, Erbium has a non-ablative photothermal effect with less discomfort and less blood loss capable of improving the local accumulation of glycogen and promoting the restoration of an adequate local pH [69]. Another type of laser that finds application in the treatment of vulvovaginal atrophy is the CO 2 laser. The CO 2 laser, unlike the Erbium laser, is able to act on the more superficial collagen, improving the vascularization of the tissues in order to obtain better integrity and elasticity of the tissues. Additionally, CO 2 lasers have been shown to improve stress urinary incontinence and vaginal prolapse, as well as vaginal dryness and dyspareunia. A recent meta-analysis by Salvatore et al. conducted in 2022 analyzed the CO 2 laser therapy efficacy for the treatment of GSM, no matter whether the patients were postmenopausal or BCS. They demonstrated that in all scores (FSFI, WHIS, and VMV scores), laser CO 2 therapy has led to a significant reduction in VVA and/or GSM symptoms. Its application showed a beneficial safety profile, and no major adverse events were reported [70].
However, the available data are short-term, and the efficacy, as well as the safety of repeated applications, are unclear. Furthermore, CO 2 laser treatment is very expensive and a procedure that is not yet widely performed by gynecologists; therefore, access to this method may be limited [71].
In 2018, Becorpi et al., in a prospective study, analyzed a sample of 20 patients for one month, treating them with CO 2 laser. They demonstrated that the laser caused changes both at a biomolecular and morphological level in the tissues by activating anti-inflammatory mechanisms [72]. Subsequently, two more prospective studies were conducted, the first by Quick et al. in 2022 and the second and most recent by Mension et al. in 2023. Both studies demonstrated that CO 2 laser is safe and effective, respectively, after 6 months and 2 years of follow-up in patients with previous BC [73,74]. Squilini's group retrospectively analyzed a cohort of 45 BCS patients, comparing them to 90 control group patients for one year. They found that fractional CO 2 vaginal laser led to a long-term improvement in GSM symptoms, even in BCS [75].
The only RCT in the literature that analyzes laser therapy in patients with GSM is the one conducted in 2021 by Gold and Collab. These were analyzed for 3 months on a group of 43 patients treated with Erbium laser or local hyaluronic acid. Both treatments were effective for patients with previous breast cancer [76]. Even if the effectiveness of vaginal lasers using both CO 2 and Erbium is confirmed in most studies, there are no studies that demonstrate their real long-term effectiveness. We have summarized the various laser therapies in Table 2.   The treatment seems to be effective. The last family of drugs that we are going to examine is selective estrogen receptor modulators (SERMs). It is a class of drugs that have activity on estrogen receptors, the most representative of which in the therapy of GSM in BCS are Tibolone, Bazedoxifene, and Ospemifene.
The LIBERATE (The Livial Intervention following Breast Cancer; Efficacy, Recurrence, and Tolerability Endpoints) study was designed to establish the safety of tibolone in women operated on for breast cancer suffering from severe menopause symptoms. The study, a double-blind, non-inferiority, multicenter RCT conducted on 3148 postmenopausal women (mean age 53 years) with a history of surgically treated breast cancers, compares therapy with tibolone (2.5 mg/day) versus placebo in terms of breast cancer recurrences. After a median follow-up of 3.1 years, a statistically significant increase in the incidence of tumor recurrence was observed in the tibolone group (237 cases vs. 165 in the placebo group; HR 1.4; CI 95% 1.1-1.7) [77].
In the literature, there are two RCTs that evaluated the activity of bazedoxifene combined with estrogens of animal origin. In the first study, healthy, postmenopausal, nonhysterectomized women (n = 652) with symptoms of moderate to severe vulvar/vaginal atrophy treated with a drug or placebo were considered. It was seen that the drug treatment had a decidedly positive efficacy in the treatment of vulvar atrophy and consequently also on the sexual hygiene of the patients, improving their quality of life. However, bazedoxifene alone, not combined with estrogen, has not been shown to improve symptoms [78].
The second study presented by Kagan et al. showed similar results in another RCT; however, neither study evaluated the safety of the drug in patients with previous breast cancer, so at present, there are no recommendations for the administration of this drug [79].
Ospemifene is a drug belonging to the class of SERMs that has the ability to act on various organs: an agonist action on the brain, vaginal epithelium, and bone; an anti-estrogenic activity on the breast; and it would appear to have no activity on the endometrium or the cardio-circulatory system.
The activity on the vaginal epithelium favors epithelial thickening, favoring its lubrication.
There are no clinical data demonstrating that ospemifene would increase the risk of BC; indeed, its anti-estrogenic activity in the breast could be protective against a possible recurrence. However, the follow-up periods of these studies were too short to conclude the long-term effects of ospemifene [80]. Barton et al. (2017) conducted a three-arm randomized controlled trial on patients with previous breast cancer or gynecological patients using DHEA gel at two different doses or a placebo. What they found is that daily use of the gel has the ability to improve vaginal dryness after 12 weeks of treatment but is unable to impact sexual function [63]. Subsequently, in a randomized double-blind study, Davis' group demonstrated that the administration of testosterone locally by ointment or cream is able to promote sexual function compared to a placebo in a group of BCS patients [66].
The latest randomized study in the literature of 2020 is the result of the activity of Hirschberg's group. This is a large multicenter prospective randomized double-blind placebo-controlled phase II study, which analyzed a group of 61 patients treated with local estrogens for 12 weeks. What was achieved was that there were no significant differences in FSH between groups (p = 0.104) with a slight increase in LH in the treatment group. No changes in E1 and E2 were observed in estrogen-treated patients, other than a slight transient increase in E3 within the first 3 weeks. It is therefore possible to state that administration of 0.005% estriol gel is safe in BCS receiving NSAI and provides clinical improvement of vaginal symptoms and signs of VVA [81]. The observational study proposed by Cold et al. included a nationwide cohort of postmenopausal women diagnosed between 1997 and 2004 with early-stage invasive estrogen receptor-positive nonmetastatic BC who received no treatment or 5 years of adjuvant endocrine therapy. We evaluated the mortality and risk of relapse associated with VET and MHT use versus no use using multivariable models adjusted for potential confounders. The study concluded that in postmenopausal women treated for early-stage estrogen receptor-positive BC, neither VET nor MHT was associated with an increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence but not mortality in patients trained on adjuvant aromatase inhibition [52].
Below, in Table 3, all the local hormone treatments are listed.
In conclusion, we deem it appropriate to say a few words about patients with nonluminal BC. Patients with non-luminal BC (HER2-positive and triple-negative) are not candidates for adjuvant HT because there has long been a consensus that they are completely independent of the estrogen signaling pathway. Chemotherapy and anti-HER2 agents are the gold standards of treatment.
Even if they do not receive AI or tamoxifen, women with non-luminal BC may experience GSM as a consequence of chemo-induced ovarian failure or age-related menopause. At first glance, the use of estrogen compounds in this population could be considered absolutely safe; however, there is no conclusive evidence in the literature to support this hypothesis [82].
According to Kenemans et al. [83], there is no significant adverse effect of HRT in the subgroup analysis of patients with ER-negative BC exposed to HRT, whereas Holmberg et al. [48] showed an increased, but not statistically significant, risk of recurrence.
Preclinical evidence has also recently demonstrated that estrogen and progesterone can circumvent the absence of their respective traditional nuclear receptors in TNBC and play an active role in cancer progression [84]. Most of the evidence comes from retrospective cohorts or subgroup analyses of studies designed primarily for luminal BC.
In conclusion, there is insufficient evidence to allow the use of systemic HRT for GSM in patients with TNBC. In our daily clinical practice, the treatment of symptoms in this subset of patients should be guided by the same guidelines approved for luminal BC, preferring non-hormonal or local therapy to systemic administration [85].

Conclusions
In BCS patients, vaginal atrophy is one of the main causes of reduced quality of life, both for individuals and couples. Patients with mild atrophy can be treated with therapy based on non-hormonal substances; however, these medicines need a long time to act and are relatively effective. In patients' refractory to non-hormonal therapy, local, low-dose estrogen administration has been shown to be the most effective treatment. Although there is strong skepticism about the use of hormone therapy in patients with previous breast cancer, this seems to be the most effective therapy to date in restoring adequate vaginal tropism. Some studies suggest a possible increase in serum estrogen levels, which may lead to an increased risk of BC recurrence. In the new guidelines, further new therapeutic strategies with mechanical and non-pharmacological action are considered, such as the vaginal laser. However, more studies are needed to evaluate. More studies are needed to evaluate the effectiveness of these new therapies.