Vulvovaginal atrophy in women with and without a history of breast cancer: Baseline data from the PatiEnt satisfactiON studY (PEONY) in Italy.

OBJECTIVES: To assess clinical characteristics of postmenopausal women with moderate/severe vulvovaginal atrophy, as well as its impact on sexual function, well-being, and quality of life, and to provide an overview of most used treatments. STUDY DESIGN: Ongoing longitudinal, observational study conducted in 17 Italian gynecology centers, involving women already treated or initiating a local vaginal estrogen therapy or ospemifene. We report baseline data for women with and without a history of breast cancer. Participants filled in self-reported questionnaires at study entry. MAIN OUTCOME MEASURES: Severity of vulvovaginal atrophy; ongoing treatments; patient-reported outcomes, including severity of symptoms, Day-to-Day Impact of Vaginal Aging (DIVA), Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), and SF-12® Health Survey. RESULTS: Overall, 334 women (20.4 % with a history of breast cancer) started or continued local therapy (61.1 %) or ospemifene (38.8 %) at study entry. Vulvovaginal atrophy was severe in 28.6 %, and was responsible for severe symptoms, particularly vulvar dryness with burning or irritation and pain during sexual intercourse. Both sexual dysfunction (FSFI≤26) (81.5 %) and sexual distress (FSDS-R ≥ 11) (74.4 %) were common. A reduction in the SF-12 mental component score was documented. Women with breast cancer more often had severe vulvovaginal atrophy (41.2 %), had more severe symptoms, and the impact of vaginal symptoms on emotional well-being, sexual functioning and self-concept/body image was greater. The majority of them (83.8 %) received ospemifene as a treatment. CONCLUSIONS: Moderate/severe vulvovaginal atrophy is a common, often neglected condition with an impact on QoL and sexuality, particularly in women with a history of breast cancer. It is important to alleviate the burden associated with the disease.

Comparison of the effect of noninvasive radiofrequency with vaginal estrogen and vaginal moisturizer in the treatment of vulvovaginal atrophy in postmenopausal women: a randomized clinical trial.

OBJECTIVE: To compare the effect of noninvasive radiofrequency (RF) with vaginal estrogen (E), and vaginal moisturizer (M) on improving vulvovaginal atrophy (VVA) in women with genitourinary syndrome of menopause. METHODS: A total of 32 postmenopausal women who met the inclusion criteria were randomized into three intervention arms to receive one of the following treatments: three sessions of noninvasive RF therapy (RF arm); intravaginal estriol cream 1 mg applied daily for 2 weeks, followed by 1 mg applied two times weekly or 1 mg of estradiol vaginal fast-dissolving film applied daily for 2 weeks, followed by 1 mg applied two times weekly (E arm); and intravaginal moisturizer two times a week (M arm). Assessments at baseline and after 4 months were conducted using Vaginal Health Index score, Vaginal Maturation, visual analog scale for VVA symptoms (dyspareunia, dryness, and burning), and Menopause Rating Scale (MRS) for urogenital symptoms. Vaginal wall biopsies were administered to participants who consented, pretreatment and posttreatment (at baseline and after 4 months of follow-up). RESULTS: After 4 months, the Vaginal Health Index showed an increase of 6.6 points in mean total score in the RF arm, also in the E arm (+7.3 points), with no significant improvement in the M arm (+1.5 points) (interaction effect: RF, E ≠ M, P < 0.001). Regarding vaginal maturation, there was a significant increase in superficial cells in the E arm (+31.3), with no significant changes in the RF (+9.3) and M (-0.5) arms (interaction effect: E ≠ M, P < 0.001). Vaginal pH decreased significantly in the E arm (-1.25), with a similar response in the RF arm (-1.7), with no significant improvement in the M arm (-0.25) (interaction effect: RF, E ≠ M, P < 0.001).There was a significant improvement in the MRS score for VVA symptoms in the three intervention arms, with no predominance of any arm, whereas the improvement in the total MRS score for urogenital symptoms showed a predominance of the RF arm (ΔRF: -7.8; ΔE: -3.5; ΔM: -2.3; RF ≠ E, M). According to histopathologic analysis, there was no statistically significant increase in glycogenation ( P = 0.691) or epithelial cone height ( P = 0.935), despite an increase in the median delta (difference between pretreatment and posttreatment) in the three intervention arms (glycogenation: RF arm Δ = +118.4%; E arm Δ = +130.9%; M arm Δ = +24.9%; epithelial cone height: RF arm Δ = +33.5%; E arm Δ = +18.6%; M arm Δ = +22.3%). CONCLUSION: The effect of noninvasive RF on the treatment of vulvovaginal symptoms of genitourinary syndrome of menopause was similar to vaginal estrogen, except for hormonal cytology, and superior to vaginal moisturizer, with improvement in some histomorphometric parameters. These findings are promising, especially for the population that cannot or prefers not to use vaginal estrogen therapy.

Microablative fractional radiofrequency for sexual dysfunction and vaginal Trophism: A randomized clinical trial.

OBJECTIVES: To evaluate Microablative Fractional Radiofrequency (MAFRF) as a possible option in treating vaginal atrophy. METHODS: This was a randomized, controlled clinical trial with postmenopausal women diagnosed with vaginal atrophy. The treatment consisted of three sessions of MAFRF, compared to vaginal estrogen administration and an untreated control group. Assessments occurred at baseline and 90 days. The primary endpoints were sexual function, evaluated by the Female Sexual Function Index (FSFI), and vaginal health, assessed by the Vaginal Health Index (VHI). Secondary outcomes included vaginal microbiota composition (Nugent score) and epithelial cell maturation (Maturation Value ‒ MV). RESULTS: One hundred and twenty women (40 in each group) were included. Concerning the FSFI, both groups, MAFRF (median 4.8 [3.6‒6.0]) and vaginal estrogen (mean 4.7 ± 1.1), experienced improved sexual desire when compared to the control group (median 3.6 [2.4‒4.8]). Regarding the total score of VHI, the authors observed an improvement in the mean of the MAFRF (23.7 ± 2.0) and vaginal estrogen groups (23.5 ± 1.9) when compared to the control (14.8 ± 2.9). The Nugent score was reduced in the MAFRF and estrogen groups (p < 0.01) compared to the control group. Lastly, the MV was modified after treatment with MAFRF (p < 0.01) and vaginal estrogen (p < 0.001). No differences existed between the MAFRF and vaginal estrogen groups in the studied variables. No adverse effects were reported following the MAFRF protocol. CONCLUSIONS: Radiofrequency was comparable in efficacy to estrogen administration for treating vulvovaginal atrophy. It deserves consideration as a viable option in managing this condition.

Vulvovaginal atrophy in the CRETA study: the healthcare professionals' perception.

OBJECTIVES: The objective is to assess the perception of gynecologists regarding patients' adherence to vulvovaginal atrophy (VVA) treatments, to evaluate the gynecologists' opinions on what their patients think about treatment adherence, and to compare the gynecologists' opinions with the patients' own perceptions within the CRETA study. METHODS: Spanish gynecologists who participated in the CRETA study were asked to fill out an online 41-item questionnaire to evaluate their views on VVA management. RESULTS: From 29 centers across Spain, 44 gynecologists completed the survey. Their mean age was 47.2 years old, two-thirds of them were women, and the average professional experience was over 20 years. According to the gynecologists, the therapy most frequently used by VVA-diagnosed women was vaginal moisturizers (45.5%), followed by local estrogen therapy (36.4%) and ospemifene (18.2%). Nevertheless, ospemifene was viewed as the therapeutic option with the most efficacy, easiest route of administration, shorter time to symptom improvement, lower percentage of dropouts, and higher treatment adherence. CONCLUSIONS: Spanish gynecologists are in general agreement with their patients regarding VVA treatment preferences and the main issues for adherence and effectiveness. However, there is an opportunity for doctor-patient communication improvement. Among the three therapeutic options evaluated, ospemifene is regarded as offering some competitive advantages.

Pharmacokinetics, safety and preliminary pharmacodynamic evaluation of DARE-VVA1: a soft gelatin capsule containing tamoxifen for the treatment of vulvovaginal atrophy.

OBJECTIVE: This study aimed to measure safety, systemic pharmacokinetics and preliminary efficacy of a vaginal tamoxifen capsule (DARE-VVA1) among postmenopausal women with moderate-to-severe vulvovaginal atrophy. METHODS: This was a randomized, placebo-controlled, double-blind, phase 1/2 study of DARE-VVA1, in four doses (1, 5, 10 and 20 mg). RESULTS: Seventeen women were enrolled and 14 completed the 8-week treatment. DARE-VVA1 was safe. All adverse events were of mild or moderate severity and distributed similarly among active and placebo groups. Plasma tamoxifen concentrations were highest among women using DARE-VVA1 20 mg, but the maximum mean (standard deviation) plasma tamoxifen concentrations on day 1 (2.66 ± 0.85 ng/ml) and day 56 (5.69 ± 1.87 ng/ml) were <14% of those measured after one oral tamoxifen dose. Active study product users had significant decreases from pre-treatment baseline in vaginal pH and proportion of vaginal parabasal cells (p = 0.04 for both endpoints), with women randomized to the 10 mg or 20 mg dose experiencing the largest treatment impact. The severity of vaginal dryness and dyspareunia decreased significantly from baseline with active study product use (p = 0.02 for both endpoints). CONCLUSIONS: DARE-VVA1 is safe and results in minimal systemic exposure to tamoxifen. Preliminary efficacy data support further development of this product.

Efficacy, tolerability, and endometrial safety of ospemifene compared with current therapies for the treatment of vulvovaginal atrophy: a systematic literature review and network meta-analysis.

IMPORTANCE: Ospemifene is a novel selective estrogen receptor modulator developed for the treatment of moderate to severe postmenopausal vulvovaginal atrophy (VVA). OBJECTIVE: The aim of the study is to perform a systematic literature review (SLR) and network meta-analysis (NMA) to assess the efficacy and safety of ospemifene compared with other therapies used in the treatment of VVA in North America and Europe. EVIDENCE REVIEW: Electronic database searches were conducted in November 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized or nonrandomized controlled trials targeting postmenopausal women with moderate to severe dyspareunia and/or vaginal dryness and involving ospemifene or at least one VVA local treatment were considered. Efficacy data included changes from baseline in superficial and parabasal cells, vaginal pH, and the most bothersome symptom of vaginal dryness or dyspareunia, as required for regulatory approval. Endometrial outcomes were endometrial thickness and histologic classifications, including endometrial polyp, hyperplasia, and cancer. For efficacy and safety outcomes, a Bayesian NMA was performed. Endometrial outcomes were compared in descriptive analyses. FINDINGS: A total of 44 controlled trials met the eligibility criteria ( N = 12,637 participants). Network meta-analysis results showed that ospemifene was not statistically different from other active therapies in most efficacy and safety results. For all treatments, including ospemifene, the posttreatment endometrial thickness values (up to 52 wk of treatment) were under the recognized clinical threshold value of 4 mm for significant risk of endometrial pathology. Specifically, for women treated with ospemifene, endometrial thickness ranged between 2.1 and 2.3 mm at baseline and 2.5 and 3.2 mm after treatment. No cases of endometrial carcinoma or hyperplasia were observed in ospemifene trials, nor polyps with atypical hyperplasia or cancer after up to 52 weeks of treatment. CONCLUSIONS AND RELEVANCE: Ospemifene is an efficacious, well-tolerated, and safe therapeutic option for postmenopausal women with moderate to severe symptoms of VVA. Efficacy and safety outcomes with ospemifene are similar to other VVA therapies in North America and Europe.

Low genitourinary tract risks in women living with the human immunodeficiency virus.

This review analyzes the clinical associations between specific low genitourinary tract clinical circumstances in perimenopausal and postmenopausal women living with human immunodeficiency virus (WLHIV). Modern antiretroviral therapy (ART) improves survival and reduces opportunistic infections and HIV transmission. Despite appropriate ART, WLHIV may display menstrual dysfunction, risk of early menopause, vaginal microbiome alterations, vaginal dryness, dyspareunia, vasomotor symptoms and low sexual function as compared to women without the infection. They have increased risks of intraepithelial and invasive cervical, vaginal and vulvar cancers. The reduced immunity capacity may also increase the risk of urinary tract infections, side-effects or toxicity of ARTs, and opportunistic infections. Menstrual dysfunction and early menopause may contribute to the early onset of vascular atherosclerosis and plaque formation, and increased osteoporosis risks requiring specific early interventions. On the other hand, the association between being postmenopausal and having a low sexual function is significant and related to low adherence to ART. WLHIV deserve a specific approach to manage different low genitourinary risks and complications related to hormone dysfunction and early menopause.

Modulation of vulvovaginal atrophy (VVA) by Gelam honey in bilateral oophorectomized rats.

Introduction: Vulvovaginal atrophy (VVA) is a common condition in post-menopausal women. Symptoms of VVA include dyspareunia, vaginal dryness, vaginal and/or vulvar itching, burning and soreness, dysuria and vaginal bleeding accompanying sexual activity. These symptoms are physiological responses to hypoestrogenicity, inducing atrophy of the vagina epithelia and sudden reduction in mucous production. Prevailing therapy for VVA is hormone replacement therapy (HRT), notably estrogen, progesterone or a combination of the two. However, using HRT is associated with an increased incidence of breast and endometrial cancer, venous thromboembolism in the lungs and legs, stroke and cardiovascular complications. Methods: This study evaluated Malaysian Gelam honey as a nutraceutical alternative to estrogen HRT (ERT) in alleviating VVA. A total of 24 female 8-weekold Sprague Dawley rats underwent bilateral oophorectomy. A minimum of 14 days elapsed from the time of surgery and administration of the first dose of Gelam honey to allow the female hormones to subside to a stable baseline and complete recovery from surgery. Vaginal tissues were harvested following a 2-week administration of Gelam honey, the harvested vagina tissue underwent immunohistochemistry (IHC) analysis for protein localization and qPCR for mRNA expression analysis. Results: Results indicated that Gelam honey administration had increased the localization of Aqp1, Aqp5, CFTR and Muc1 proteins in vaginal tissue compared to the menopause group. The effect of Gelam honey on the protein expressions is summarized as Aqp1>CFTR>Aqp5>Muc1. Discussion: Gene expression analysis reveals Gelam honey had no effect on Aqp1 and CFTR genes. Gelam honey had up-regulated Aqp5 gene expression. However, its expression was lower than in the ERT+Ovx group. Additionally, Gelam honey up-regulated Muc1 in the vagina, with an expression level higher than those observed either in the ERT+Ovx or SC groups. Gelam honey exhibits a weak estrogenic effect on the genes and proteins responsible for regulating water in the vaginal tissue (Aqp1, Aqp5 and CFTR). In contrast, Gelam honey exhibits a strong estrogenic ability in influencing gene and protein expression for the sialic acid Muc1. Muc1 is associated with mucous production at the vaginal epithelial layer. In conclusion, the protein and gene expression changes in the vagina by Gelam honey had reduced the occurrence of vaginal atrophy in surgically-induced menopause models.

New developments in the management of vulvovaginal atrophy: a comprehensive overview.

INTRODUCTION: Proper recognition and individualized therapy of vulvovaginal atrophy (VVA) is paramount. AREAS COVERED: Assessment of VVA should be performed using several questionnaires in combination with wet mount microscopy to determine Vaginal Cell Maturation Index (VCMI) and infections. PubMed searches were carried out between 1 march 2022 and 15 October 2022.Low dose vaginal estriol seems safe, efficient, and could be used in patients with contraindications for steroid hormones such as women with a history of breast cancer, and should therefore be considered as first choice hormonal treatment, when non-hormonal treatments fail. New estrogens, androgens, and several Selective Estrogen Receptor Modulators (SERMs) are being developed and tested. Intravaginal Hyaluronic Acid (HA) or Vit D can help women who can't or don't want to use hormones. EXPERT OPINION: Proper treatment is not possible without a correct and full diagnosis, including microscopy of the vaginal fluid. Low dose vaginal estrogen treatment, especially with estriol, is very efficient and is preferred in most women with VVA. Oral ospemifene and vaginal dihydroepiandrosterone (DHEA) are now considered efficient and safe alternative therapies for VVA. More safety data are waited for several SERMs and for a newly introduced estrogen: estetrol (E4), although so far no major side effects were seen from these drugs. Indications for laser treatments are questionable.

Vaginal laser therapy versus hyaluronic acid suppositories for women with symptoms of urogenital atrophy after treatment for breast cancer: A randomized controlled trial.

BACKGROUND: Urogenital atrophy affects >50 % of women after breast cancer (BC) and there is reluctance to use local estrogen for this group. Hormone-free therapies like intravaginal laser therapy and hyaluronic acid suppositories have been shown to produce symptom relief in women with BC and urogenital atrophy, but have not been tested against each other. The aim of this study was to compare these nonhormonal modalities in women with urogenital atrophy after BC in a randomized fashion. STUDY DESIGN: We randomly assigned 43 women (aged 49-58 years, mean age 54 years) with urogenital atrophy and a history of BC to receive intravaginal laser therapy (2 courses within 1 month) or hyaluronic acid suppositories (3 times/week continuously for three months). The primary endpoint was score on the Vaginal Health Index after 3 months. Secondary endpoints were subjective bother on a numeric rating scale for all urogenital atrophy domains, quality of life, sexual health and pelvic organ prolapse symptoms using validated questionnaires. RESULTS: Of the 43 women who participated, 22 were randomized to intravaginal laser therapy, and 21 to vaginal suppositories. At 3 months score on the Vaginal Health Index had improved significantly in both groups (p = 0.001), without a significant difference between treatment groups (p = 0.232). Significant improvement was also seen in both groups for subjective bother of urogenital atrophy, quality of life and sexual health, without significant differences between laser or hyaluronic acid therapy. CONCLUSIONS: Both intravaginal laser therapy and hyaluronic acid suppositories are effective treatment options for women after BC suffering from urogenital atrophy. No difference was found between treatment regimens. CLINICALTRIALS: gov identifier: NCT03816735, https://clinicaltrials.gov/ct2/show/NCT03816735.

Intravaginal dehydroepiandrosterone for genitourinary symptoms of the menopause: Is the evidence sufficient?

Intravaginal dehydroepiandrosterone (DHEA) is a locally metabolised estrogen and androgen precursor, licensed in 2018 in the EU for moderate to severe vulvovaginal atrophy in postmenopausal women. A literature search revealed four original trials suitable for appraisal, three evaluating change in dyspareunia or dryness as a primary outcome, one evaluated safety as a primary outcome. In two trials of 255 and 558 women without cancer, the benefit of placebo (nightly vaginal suppositories with a lipophilic base) was a 0.9 and 1 point reduction in dyspareunia as measured on a 3 point scale, an unvalidated outcome measure. With nightly DHEA, dyspareunia was reduced by an additional 0.4 points compared to placebo. When 464 women with gynaecological cancer were randomised, those using nightly plain moisturiser gel reported a reduction of 'most bothersome symptom' (either dyspareunia or dryness) of 1.5 points on a 3 point scale. Those using nightly DHEA reported an additional symptom reduction of 0.3 points. This is also an unvalidated outcome measure. Data evaluating the efficacy of DHEA over placebo is unconvincing and based on unvalidated primary outcome measures that also do not reflect the complex psycho-sexual and socio-cultural components of genitourinary menopausal symptoms. The efficacy and safety data excluded women taking systemic HRT, applies to postmenopausal, not perimenopausal, women and had relatively short follow up. It is important further independent trials use sophisticated and validated assessment tools to better establish the efficacy, safety and cost effectiveness of intravaginal DHEA in clinically representative groups of women before being routinely prescribed.

Efficacy of interventions to manage sexual dysfunction in women with cancer: a systematic review.

IMPORTANCE: Cancer and its treatment negatively affect female sexual health and function. The prevalence of female sexual dysfunction after cancer is between 33% and 43%. Numerous studies have addressed treatment options for sexual dysfunction in women with cancer, but it still remains a challenge to select the most efficacious option for patients. OBJECTIVE: To compile and appraise recent evidence of any interventions for managing sexual dysfunction in female cancer survivors. EVIDENCE REVIEW: A literature search of the electronic databases MEDLINE, EMBASE, PsycINFO, and Cochrane Central Register of Controlled Trials (January 2011 to February 2021) was conducted using general search terms of "women", "cancer", "intervention", "sexual dysfunction". We included randomized controlled trials (RCTs) and uncontrolled before-after studies that evaluated the efficacy of intervention for female sexual dysfunction in women with history of cancer. Methodological quality of studies was assessed using Risk of Bias (RoB) 2.0 for RCTs and National Institutes of Health (NIH) assessment tools for uncontrolled before-after studies. FINDINGS: Thirty-six studies were included for qualitative synthesis (14 RCTs (n = 1284), 17 uncontrolled trials (n = 589), and 5 cohort studies (n = 497). Only four studies were at low risk of bias. Topical interventions (vaginal gels or creams) were able to alleviate vaginal dryness and dyspareunia, with intravaginal dehydroepiandrosterone (DHEA) (6.5 mg) gel showing evidence of improved sexual function. Evidence for estriol-lactobacilli vaginal tablets was unreliable due to a small-scale study. Psychoeducational therapy (internet-based cognitive behavioral therapy [CBT]) studies typically were at high risk of bias, but all displayed significant improvements of sexual function. Both laser therapy (fractional CO2 and erbium) and multimodal approach studies were at concerning risk of bias, although suggesting beneficial effects on sexual function. CONCLUSIONS AND RELEVANCE: The most reliable evidence for improvement was from a study of DHEA vaginal gel, but in general, gels or creams were useful in reducing dyspareunia. Pharmacological, psychoeducational, laser therapy, and multimodal approaches demonstrated potential in managing cancer-related sexual issues, but most were small in size (10-70 participants), with moderate to high risk of bias. Therefore, large-scale, double-blind, RCTs with long-period follow-up, and at low risk of bias are needed to show efficacy for these interventions.

Video Summary : http://links.lww.com/MENO/A912 .

Topical estrogens and non-hormonal preparations for postmenopausal vulvovaginal atrophy: An EMAS clinical guide.

INTRODUCTION: Vulvovaginal atrophy (VVA) is a chronic condition caused by estrogen deficiency. It affects around 50% of postmenopausal women, reducing their general and sexual quality of life as well as the quality of their personal relationships. AIM: The aim of this clinical guide is to set out an individualized approach to the management of VVA with topical estrogens and non-hormonal preparations. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: An individualized approach is required for the management of VVA. Topical low-dose estrogens are effective and also alleviate urinary incontinence and prevent recurrent urinary tract infections. Women should not be denied long-term use of topical estrogens as long as they feel that this treatment is of benefit to them, because the safety data are reassuring. Non-hormonal preparations (lubricants and moisturizers) should be the first-line treatment for VVA in women taking adjuvant endocrine therapies for cancers considered to be hormone-dependent. They can be used over the long term.

The Efficacy of Vaginal Laser and Other Energy-based Treatments on Genital Symptoms in Postmenopausal Women: A Systematic Review and Meta-analysis.

OBJECTIVE: This systematic review examined energy-based treatments of the vagina for postmenopausal vaginal symptoms. DATA SOURCES: We performed a systematic review from April 2017 (the end date of our previous review) to April 2020, searching Medline, Embase, and Scopus. METHODS OF STUDY SELECTION: The inclusion criteria were all randomized studies, prospective studies with >10 cases, and retrospective studies with >20 cases published in English or French that assessed change in postmenopausal vaginal symptoms and/or sexual function in women after energy-based vaginal treatments. Meta-analyses were performed on randomized data. TABULATION, INTEGRATION, AND RESULTS: Of the 989 results retrieved, 3 randomized studies, 16 prospective studies, and 7 retrospective studies were included in the review, representing data from 2678 participants. Pooled data from 3 randomized controlled trials show no difference between vaginal laser and topical hormonal treatments for change in vaginal symptoms (-0.14, 95% confidence interval -1.07 to 0.80) or sexual function scores (2.22, 95% confidence interval -0.56 to 5.00). Furthermore, no difference among vaginal laser, topical hormone, and lubricant was demonstrated in sexual function (p = .577). As in our previous review, non-randomized data support energy-based treatments in improving vaginal symptoms, sexual function, and clinician-reported outcomes. No severe adverse events were reported in the included studies. Significant heterogeneity of data arising from differing measures and reported outcomes continues to be an issue, with data remaining low quality, with high risk of bias, and no double-blind or placebo-controlled randomized trials yet reported, although 1 has now completed recruitment. CONCLUSION: There are 3 randomized trials comparing energy-based systems with hormonal treatment, with no clinical difference in these 2 approaches. Although prospective data continue to show promising outcomes, without strong evidence from well-powered, double-blind placebo-controlled trials to determine the efficacy of treatment compared with placebo, the use of energy-based treatments should continue to be undertaken in research studies only, with high-quality studies essentially free from bias (International Prospective Register of Systematic Review registration number: 178346).

A single-arm, prospective trial investigating the effectiveness of a non-hormonal vaginal moisturizer containing hyaluronic acid in postmenopausal cancer survivors.

PURPOSE: To assess the feasibility and efficacy of a non-hormonal hyaluronic acid (HLA) vaginal gel in improving vulvovaginal estrogen-deprivation symptoms in postmenopausal women with a history of hormone receptor-positive (HR+) cancer. METHODS: For this single-arm, prospective longitudinal trial, we identified disease-free patients with a history of HR+ breast cancer treated with aromatase inhibitors or HR+ endometrial cancer treated with surgery and postoperative radiation. Participants used HLA daily for the first 2 weeks, and then 3×/week until weeks 12-14; dosage was then increased to 5×/week for non-responders. Vulvovaginal symptoms and pH were assessed at 4 time points (baseline [T1], 4-6 weeks [T2], 12-14 weeks [T3], 22-24 weeks [T4]) with clinical evaluation, the Vaginal Assessment Scale (VAS), Vulvar Assessment Scale (VuAS), Female Sexual Function Index (FSFI), and Menopausal Symptom Checklist (MSCL). RESULTS: Of 101 patients, mean age was 55 years (range, 31-78), 68% (n = 69) were partnered, and 60% (n = 61) were sexually active. In linear mixed models, VAS/VuAS scores significantly improved at all assessment points (all p < 0.001). MSCL scores similarly improved (all p < 0.001). FSFI scores significantly improved from T1 to T2 (p < 0.03), T3 (p < 0.001), and T4 (p < 0.001). Severe vaginal pH (> 6.5) decreased from 26% at T1 to 19% at T4 (p = 0.18). CONCLUSIONS: HLA moisturization improved vulvovaginal health/sexual function of cancer survivors. While HLA administration 1-2×/week is recommended for women in natural menopause, a 3-5×/week schedule appears to be more effective for symptom relief in cancer survivors.

Changes in serum estradiol levels with Estring in postmenopausal women with breast cancer treated with aromatase inhibitors.

BACKGROUND: Anti-estrogen therapy is an effective intervention for preventing reoccurrence of hormone receptor-positive breast cancer in women. However, the side effects of anti-estrogen therapy, including urogenital symptoms, have been reported to cause significant morbidity. There is controversial data, mainly due to small sample sizes, reporting on the safety and efficacy of using vaginal estrogen to treat urogenital symptoms in patients on aromatase inhibitor therapy. METHODS: We proposed a prospective trial to measure the change in blood estradiol levels in postmenopausal women with hormone receptor-positive breast cancer undergoing treatment with aromatase inhibitors when treated with vaginal estrogen preparation, Estring, for their urogenital symptoms. Only 8 prospective patients were enrolled, and the study was amended to include 6 retrospective patients who were treated similarly. Blood estradiol levels were measured at baseline and at week 16 for all patients. RESULTS: The median age for all patients was 55 years, and the majority of them were treated with anastrozole. There was no significant difference between baseline and week 16 estradiol levels (p = 0.81). In addition, patients in the prospective group reported subjective improvement in their vaginal dryness symptoms questionnaires. CONCLUSIONS: The vaginal estrogen preparation, Estring, did not cause persistent elevations in serum estradiol levels and might be a safer option for women with significant urogenital symptoms requiring estrogen therapy. IMPLICATIONS FOR CANCER SURVIVORS: Vaginal estrogen preparation, Estring, might be an option for women with hormone receptor positive breast cancer who have persistent urogenital symptoms.

Ospemifene in clinical practice for vulvo-vaginal atrophy: results at 3 months of follow-up of use.

OBJECTIVE: To assess the effect of ospemifene 60 mg/day in vulvovaginal atrophy (VVA) in postmenopausal women under conditions of routine clinical practice after 3 months of follow-up. METHODS: The AYSEX study is a Spanish observational, prospective, and unicentric study in which 5 gynecologists recruited postmenopausal women with VVA in routine clinical practice treated with ospemifene 60 mg/day as an appropriate therapeutic option. Vaginal health, sexual health, dryness, dyspareunia, quality of life, and satisfaction with treatment were assessed at baseline and after three months using validated scales. RESULTS: A total of 100 postmenopausal women cytologically and clinically diagnosed with VVA were included in the study. After 3 months of treatment with ospemifene, vaginal health index increased and vaginal pH, dryness, and dyspareunia decreased significantly (p < .0001). A significant improvement was observed in sexual function and quality of life. CONCLUSIONS: This study in routine clinical practice conditions confirms the results previously reported by randomized controlled trials, including a significant improvement in VVA, sexual function, quality of life, and satisfaction with the treatment.

Vaginal Er:YAG laser application in the menopausal ewe model: a randomised estrogen and sham-controlled trial.

OBJECTIVE: To describe effects of non-ablative erbium-doped:yttrium-aluminium-garnet (Er:YAG) laser on vaginal atrophy induced by iatrogenic menopause in the ewe. DESIGN: Animal experimental, randomised, sham and estrogen-treatment controlled study with blinding for primary outcome. SETTING: KU Leuven, Belgium. SAMPLE: Twenty-four ewes. METHODS: Menopause was surgically induced, after which the ewes were randomised to three groups receiving vaginal Er:YAG laser application three times, with a 1-month interval; three sham manipulations with a 1-month interval; or estrogen replacement and sham manipulations. At given intervals, ewes were clinically examined and vaginal wall biopsies were taken. Vaginal compliance was determined by passive biomechanical testing from explants taken at autopsy. MAIN OUTCOME MEASURES: Vaginal epithelial thickness (primary), composition of the lamina propria (collagen, elastin, glycogen and vessel content), vaginal compliance, clinical signs. RESULTS: Animals exposed to Er:YAG laser application and sham manipulation, but not to estrogens, displayed a significant and comparable increase in vaginal epithelial thickness between baseline and 7 days after the third application (69% and 67%, respectively, both P < 0.0008). In laser-treated ewes, temporary vaginal discharge and limited thermal injury were observed. Estrogen-substituted ewes displayed a more prominent increase in epithelial thickness (202%; P < 0.0001) and higher vaginal compliance (P < 0.05). None of the interventions induced changes in the lamina propria. CONCLUSIONS: Vaginal Er:YAG laser has comparable effect to sham manipulation in menopausal ewes. TWEETABLE ABSTRACT: Vaginal Er:YAG laser has comparable effect to sham manipulation in menopausal ewes #LASER #GSM #RCT.

Estradiol softgel inserts for the treatment of VVA symptoms: an expert opinion.

INTRODUCTION: Vulvar and vaginal atrophy (VVA) affects up to two thirds of postmenopausal women, with symptoms of vaginal dryness, dyspareunia, and vulvar/vaginal irritation. Despite the availability of various treatments, women express dissatisfaction with their options. An estradiol (E2; 4-µg and 10-µg) softgel vaginal insert was approved by the Food and Drug Administration (FDA) to treat moderate to severe dyspareunia, a symptom of VVA, due to menopause. These inserts were designed to treat VVA effectively and safely while avoiding some of the drawbacks of other administration methods. AREAS COVERED: This article reviews the physical characteristics and pharmacokinetic data of the E2 softgel vaginal insert. Primary and secondary efficacy endpoints and safety data are reviewed from the pivotal REJOICE trial (NCT02253173), and substudies that explore response rates, changes in vaginal epithelium by visual assessment, efficacy in patient subgroups, effects on sexual function, and patient satisfaction compared with other treatments. EXPERT OPINION: The E2 insert shows that vaginal drug delivery is an optimal route of administration for locally treating VVA. This E2 softgel vaginal insert is a safe and effective treatment for symptoms of postmenopausal VVA. The E2 insert's pharmacokinetic characteristics are related to its unique formulation, rapid dissolution, and minimal systemic absorption. ABBREVIATIONS: AE: adverse event; AUC: area under the concentration-time curve; BMI: body mass index; Cavg: average concentration; CI: confidence interval; Cmax: maximum concentration; Cmin: minimum concentration; E2: estradiol; FDA: Food and Drug Administration; FSFI: Female Sexual Function Index; GSM: genitourinary symptoms of menopause: MBS: most bothersome symptom; NAMS: North American Menopause Society; OR: odds ratio; PI: pulsatility index; PK: pharmacokinetic; REVIVE: Real Women's Views of treatment options for menopausal Vaginal changEs; RI: resistance index; ROC: receiver operating characteristic; TEAE: treatment-emergent adverse event; tmax: time to maximum concentration; VVA: vulvar and vaginal atrophy.

Effect of estradiol vaginal gel on vaginal atrophy in postmenopausal women: A randomized double-blind controlled trial.

AIM: To evaluate the efficacy and safety of 25 µg of estradiol gel on postmenopausal vaginal tissue. METHODS: This randomized double-blind controlled trial included postmenopausal women with vaginal atrophy who attended our menopause clinic during July 2017-January 2018. Women were randomly assigned to the estradiol gel group or control group (K-Y® Jelly). Treatment consisted of 2 mL of product applied intravaginally daily for 2 weeks, and two doses per week for the next 6 weeks. The most bothersome symptom (MBS), vaginal health index (VHI), vaginal pH, vaginal maturation index, vaginal maturation value (VMV), female sexual function index (FSFI), serum estradiol level and endometrial thickness were evaluated at baseline, 4 and 8 weeks. RESULTS: Seventy-five of 80 women completed the trial. After 8 weeks of treatment, VMV, VHI, vaginal pH and FSFI improved significantly in the estradiol group, with no observed change in the control group. The MBS was decreased in both groups with no significant difference between groups. Serum estradiol level and endometrial thickness were not significantly different between groups at baseline or at week 8. CONCLUSION: Estradiol vaginal gel demonstrated an ability to reverse vaginal atrophy with a high safety profile and low systemic absorption of estradiol.