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Objective: This study aimed to evaluate the self-reported satisfaction of Spanish postmenopausal women currently treated for vulvovaginal atrophy (VVA) symptoms., Methods: The CRETA (CRoss sectional European sTudy on Adherence) is a multicenter cross-sectional study conducted in 29 public and private hospitals in Spain, which enrolled postmenopausal women receiving treatment with ospemifene, local hormone therapy (HT) or vaginal moisturizers for VVA. After the prior informed consent of the patients, sociodemographic and treatment perception data were collected using a structured questionnaire., Results: Among 752 women who completed the survey, the satisfaction score was significantly higher for the group treated with ospemifene (mean 8.3 ± 1.4) compared with the local HT group (7.2 ± 1.7) and the vaginal moisturizer group (6.5 ± 2.1) according to a 10-point Likert scale ( p  < 0.0001). Compared to vaginal moisturizers and local HT, participants treated with ospemifene reported the highest adherence (96.7% vs. 70.2% and 78.6%, respectively) and the lowest number of missed doses in the last month (0.6 ± 1.3 standard deviation [SD] vs. 3.5 ± 4.3 SD and 2.0 ± 2.8 SD, respectively) ( p  < 0.0001). Ospemifene was significantly perceived as easy to use (83.9% vs. 44.9% and 58.6%, respectively; p  < 0.0001), efficacious in reducing the time to relieve symptoms (17.1% vs. 7.0% and 6.7%, p  = 0.0005 and p  = 0.0006, respectively) and convenient for sexual life (53.1% vs. 25.6% and 42.3%, p  < 0.0001 and p  = 0.0234, respectively)., Conclusions: Among postmenopausal women with VVA, treatment with ospemifene has the most positive perceptions and the highest overall satisfaction level and could be an optimal therapeutic approach, maximizing patient adherence.

Primary enteric type adenocarcinomas of the vagina are extremely rare. We present a 63-year-old woman who had a polypoid mass localized to the distal vagina. The lesion was composed of a columnar glandular cell proliferation with focal cribriforming, reminiscent of tubular adenoma. Immunohistochemical stains were notable for expression of enteric markers (CDX2 and KRT20), as well as negativity for Mullerian markers (PAX8, ER, and PR), diffuse expression for p16, and positivity for high-risk HPV mRNA expression. Ultimately, a diagnosis of vaginal primary HPV-associated enteric type adenocarcinoma was rendered for this unusual lesion. To our knowledge, no prior cases of HPV-associated enteric type adenocarcinomas of the vagina have been described before., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.

Background/aim: Vaginal intraepithelial neoplasia (VaIN) is a rare human papillomavirus (HPV)- related premalignant condition. VaIN lesions are diagnosed histologically through colposcopy-guided biopsies of suspicious areas, conduced by gynecologists with expertise in lower genital tract diseases. The present study aimed to evaluate the accuracy of colposcopy in the diagnosis of VaIN of any grade., Patients and Methods: We conducted a retrospective analysis on a cohort of 149 women diagnosed with low grade (LG)-VaIN (VaIN1) and high grade (HG)-VaIN (VaIN2-3) between 2010 and 2022 at the "Regional Referral Center for Prevention, Diagnosis and Treatment of HPV-related Genital Disorders", Ospedale Maggiore Policlinico, Milan, Italy. All women had been referred to our center for an abnormal Pap smear or as part of routine follow-up of other HPV-related diseases and had undergone a vaginal biopsy under colposcopic guidance., Results: The distribution of the histological grades of VaIN lesions was the following: 62 women (41.6%) were diagnosed with VaIN1, 51 (34.2%) with VaIN2, and 36 (24.2%) with VaIN3. Grade II (major) abnormal colposcopic patterns were recorded in 71 cases (47.7%) and were more commonly observed in women with VaIN3 (80.6%). However, we found a poor and not statistically significant association between colposcopic and histological grade of VaIN. The sensitivity, specificity, positive predictive value, and negative predictive value of colposcopy for histologically confirmed VaIN were 56.3%, 64.5%, 69% and 51.2%, respectively. The overall diagnostic accuracy of colposcopy was 59.7%., Conclusion: Colposcopy-guided biopsy plays an important role in the diagnosis of VaIN and in the distinction between low and high-grade lesions. Our data show that major colposcopic abnormalities moderately correlate with HG-VaIN and that grade I colposcopic findings do not exclude HG-VaIN, especially VaIN2. Targeted biopsies of suspicious vaginal areas must be performed in all women with an abnormal Pap smear., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: To investigate the main symptoms of female sexual dysfunction (FSD) and lower urinary tract symptoms associated with vulvovaginal atrophy (VVA) symptoms as the core symptoms of genitourinary syndrome of menopause., Methods: We extracted the data of 4134 Japanese women aged 40-79 years who participated in the GENitourinary syndrome of menopause in JApanese women (GENJA) study. All participants responded to web-based questionnaires assessing their health situation, including the Vulvovaginal Symptoms Questionnaire, the Female Sexual Function Index (FSFI), and the Core Lower Urinary Tract Symptom Score. Multivariable regression and multivariable logistic regression analyses were applied to analyze the association between VVA symptoms and FSD, and between VVA symptoms and lower urinary tract symptoms., Results: Multivariable regression analysis revealed that VVA symptoms were associated with lower scores for arousal, lubrication, orgasm, satisfaction, and pain domains in the FSFI in sexually active women (p < 0.01). Regression coefficients were higher for lubrication and pain domains than for the other domains. Multivariable logistic regression analysis revealed that women reporting VVA symptoms were more likely to have increased daytime urinary frequency, nocturia, urgency, slow stream, straining to void, feeling of incomplete emptying, bladder pain, and feeling a bulge/lump from or in the vagina (p < 0.05). Adjusted odds ratios were particularly high for straining to void, feeling of incomplete emptying, and bladder pain., Conclusions: Vulvovaginal atrophy symptoms were significantly associated with decreased lubrication and dyspareunia in FSD, and urinary symptoms of straining to void, feeling of incomplete emptying, and bladder pain., (© 2023 The Japanese Urological Association.)

Estrogen withdrawal, which occurs with the cessation of ovulation, causes genitourinary syndrome of menopause in up to 50-85% of women. Symptoms may profoundly impact quality of life and sexual function, interfering with enjoyment of sex in up to three out of four individuals. Topical estrogens have been found to provide symptom relief with minimal systemic absorption and appear to be superior to systemic therapy as what regards genitourinary symptoms. However, conclusive data on their appropriateness in postmenopausal women with a history of endometriosis is not available and the hypothesis that exogenous estrogen stimulation may reactivate endometriotic foci or even promote their malignant transformation is still open. On the other hand, endometriosis affects around 10% of premenopausal women, many of which may be exposed to an acute hypoestrogenic depletion even before spontaneous menopause occurs. This considered, excluding on principle patients with a history of endometriosis from first-line treatment for vulvovaginal atrophy would mean excluding a considerable percentage of the population from adequate care. More robust evidence is urgently needed in these regards. Meanwhile, it would appear reasonable to tailor the prescription of topical hormones in these patients, taking into account the entity of symptoms and the impact such symptoms have on patients' quality of life, as well as the form of endometriosis and the possible risks hormonal may entail. Moreover, the application of estrogens on the vulva instead of the vagina could be efficacious, while outweighing the possible biological cost of hormonal treatment in women with a history of endometriosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Postmenopausal vaginal symptoms affect over 60% of women and may substantially impact a woman's quality of life. Since 2012, fractional CO 2 laser has been suggested as a treatment for this indication. Structural assessment of vaginal epithelium using microscopic biopsy examination has been used as a primary outcome measure and surrogate determinant of success of vaginal laser in previous clinical studies., Objective: This study aimed to report the effects of laser compared with sham treatment on human vaginal epithelium from postmenopausal women using microscopic examination of tissue biopsies., Study Design: This single-center double-blind, sham-controlled randomized controlled trial was performed in a tertiary hospital in Sydney, Australia. A total of 49 postmenopausal women who were symptomatic of at least 1 vaginal symptom (vaginal dryness, burning, itching; dyspareunia; or dryness) were randomized to either laser or sham treatment. For this nested histologic study, participants had a pre- and post-treatment vaginal wall biopsy collected. Biopsy samples were analyzed by 3 independent specialist gynecologic pathologists and categorized as Type 1 (well-estrogenized), 2 (poorly estrogenized), or 3 (combination) mucosae. Other outcomes assessed included symptom severity (visual analog scale for symptoms including most bothersome symptom, and Vulvovaginal Symptom Questionnaire) and Vaginal Health Index. Prespecified secondary analyses of data were performed. Categorical data were analyzed using the Pearson chi-square test (or Fisher exact test if <5 in any category) or related-samples McNemar test for paired nonparametric data. Nonparametric, continuous variables were assessed using Wilcoxon signed-rank test or Mann-Whitney U test, and parametric variables with t test or 1-way analysis of variance as appropriate. All analyses were performed using SPSS software version 26.0 (IBM Corp, Armonk, NY)., Results: There was no significant difference in microscopic features of vaginal epithelium following laser or sham treatment (P=.20). Further subgroup analyses of age, menopause type, duration of reproductive life, time since menopause and BMI, still demonstrated no significant difference between laser and sham groups in histological category of vaginal epithelium. Microscopic features at pre-treatment vaginal biopsy were Type 1 in 27% (13/49). There was no significant difference in VAS score for overall vaginal symptom between those classified as Type 1 vs. Type 2/3 (VAS score overall: Type 1 vs. Type 2/3, (48.1 [95% CI 27.0, 69.2] vs. 61.5 [95% CI 49.8, 73.3]; P=.166)., Conclusion: Data from this double-blind, sham-controlled randomized controlled trial demonstrate that fractional CO 2 laser and sham treatment have a comparable histologic effect on vaginal tissue that is not significantly different. Fractional CO 2 laser is not significantly different from sham treatment and should not be recommended for clinical use for postmenopausal vaginal symptoms., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Menopause and the decline in systemic estrogen are associated with the development of pelvic floor disorders, such as prolapse, urinary incontinence, overactive bladder, and vulvovaginal atrophy symptoms. Past evidence suggests that postmenopausal women with symptomatic prolapse gain benefit from the preoperative application of intravaginal estrogen, but it is unknown whether they would experience improvement in other pelvic floor symptoms when treated with intravaginal estrogen., Objective: This study aimed to determine the effects of intravaginal estrogen (compared with placebo) on stress and urgency urinary incontinence, urinary frequency, sexual function and dyspareunia, and vaginal atrophy symptoms and signs in postmenopausal women with symptomatic prolapse., Study Design: This was a planned ancillary analysis of a randomized, double-blind trial, "Investigation to Minimize Prolapse Recurrence Of the Vagina using Estrogen," which included participants with ≥stage 2 apical and/or anterior prolapse scheduled for transvaginal native tissue apical repair at 3 US sites. The intervention was 1 g conjugated estrogen intravaginal cream (0.625 mg/g) or identical placebo (1:1), inserted nightly for 2 weeks and then twice weekly for ≥5 weeks total before surgery and continued twice weekly for 1 year postoperatively. For this analysis, question responses were compared from participants' baseline and preoperative visits: lower urinary tract symptoms (Urogenital Distress Inventory-6 Questionnaire); sexual health questions, including dyspareunia (Pelvic Organ Prolapse/Incontinence Sexual Function Questionnaire-IUGA-Revised); and atrophy-related symptoms (dryness, soreness, dyspareunia, discharge, and itching; each scored 1-4, 4 being quite a bit bothersome). Masked examiners assessed vaginal color, dryness, and petechiae (each scored 1-3, total range 3-9, with 9 being the most estrogenized appearing). Data were analyzed by intent to treat and "per protocol" (ie, those adherent with ≥50% of expected intravaginal cream use, per objective tube before and after weights)., Results: Of 199 participants randomized (mean age of 65 years) and contributing baseline data, 191 had preoperative data. The characteristics were similar between groups. Total Urogenital Distress Inventory-6 Questionnaire scores showed minimal change during this median time of 7 weeks between baseline and preoperative visits, but for those with at least moderately bothersome baseline stress urinary incontinence (32 in the estrogen group and 21 in the placebo group), 16 (50%) in the estrogen group and 9 (43%) in the placebo group showed improvement (P=.78). In addition, 43% of participants in the estrogen group and 31% of participants in the placebo group showed improvement in urgency urinary incontinence (P=.41), and 41% of participants in the estrogen group and 26% of participants in the placebo group showed improvement in urinary frequency (P=.18). There was minimal change in the Pelvic Organ Prolapse/Incontinence Sexual Function Questionnaire-IUGA-Revised scores among sexually active women; dyspareunia rates did not differ between intravaginal estrogen and placebo at the preoperative assessment: 42% and 48%, respectively (P=.49). The maximum score for most bothersome atrophy symptom (among those with baseline symptoms and adherent to study cream) improved slightly more with intravaginal estrogen (adjusted mean difference, -0.33 points; 95% confidence interval, -0.98 to 0.31), but this was not statistically significant (P=.19). However, on examination, among adherent participants, objective signs of atrophy were more improved with intravaginal estrogen treatment (+1.54 vs +0.69; mean difference, 0.85; 95% confidence interval, 0.05-1.65; P=.01)., Conclusion: Despite objective changes in the vaginal epithelium consistent with increased estrogenization among drug-adherent participants, the results were inconclusive regarding whether 7 weeks of preoperative intravaginal estrogen cream in postmenopausal women with symptomatic pelvic organ prolapse was associated with improved urinary function, sexual function, dyspareunia symptoms, and other symptoms commonly attributed to atrophy. Additional study is needed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Anticancer treatments induce vulvovaginal complications that alter the quality of life and sexuality of patients. New technologies, such as photobiomodulation, could address this problem, for which few effective therapeutic solutions exist. The objective of this study was to describe the characteristics of patients seeking treatment and to observe the effects of photobiomodulation. This is a prospective cohort of patients treated for cancer, in failure of first-line medical treatment, managed at the University Hospital of Nîmes. The history, symptoms and impact of the disorders on their quality of life were collected. At follow-up, improvement was assessed using the PGI-I and FSFI questionnaires. Twenty-eight patients were treated. They were all menopausal, half of them after anticancer treatments [chemotherapy (78%), radiotherapy (36%), hormone therapy (36%)]. The main symptom reported was vaginal dryness (72%). Seventy-one percent of patients (n=20) felt that their daily life was affected≥8/10. All patients had sexual dysfunction. Twenty-two patients received at least 6 sessions of photobiomodulation. Seventy-two percent (n=18) of patients felt better or much better after treatment (PGI-I≤2). The median improvement estimated by the patients was 65% (Q1=50%; Q3=72.5%). There was also a significant clinical improvement. No serious adverse events were reported. Due to the small number of patients in a heterogeneous population with no control group, we cannot extrapolate our results. However, the objective was to assess the status of these pathologies and the contribution of photobiomodulation in patients who have failed first-line treatment; and these results are encouraging., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Full-length vaginal (FLV) brachytherapy for patients with endometrial cancer and high-risk features should be considered as per the American Brachytherapy Society to reduce distal vaginal recurrence in patients with endometrial cancers with papillary serous/clear cell histologies, grade 3 status, or extensive lymphovascular invasion. We sought to investigate this patient population and report outcomes of treatment with high-dose-rate (HDR) brachytherapy in women treated with FLV brachytherapy versus partial-length vaginal (PLV) brachytherapy., Methods and Materials: With institutional review board approval, we identified patients with endometrial cancer meeting American Brachytherapy Society criteria of high-risk features treated with adjuvant HDR between 2004 and 2010. HDR doses were 21Gy in 3 fractions delivered to either the full-length or partial-length vagina. Acute and late toxicities were evaluated using the Radiation Therapy Oncology Group scale and Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer grading, respectfully. Vaginal recurrences were assessed by physical examination and pap smears. Statistical analyses were performed using SPSS version 23 software., Results: Of 240 patients treated with HDR brachytherapy, 121 were treated with FLV brachytherapy, and 119, with PLV brachytherapy. The median follow-up was 9.5 years (range, 8-11 years) for FLV patients and 8.5 years (range, 7-10 years) for PLV patients; 0% of patients had vaginal recurrences, and 1.4% and 0.9% had proximal vaginal recurrences, respectively (P = .54). All patients treated with FLV brachytherapy developed grade 3 mucositis of the lower vagina/introitus (P < .0001) and had increased analgesics use compared with those treated with PLV brachytherapy (P < .0001). In total, 23% of patients treated with FLV brachytherapy developed grade 3 stenosis of the lower vagina/introitus, in contrast to 0% of patients treated with PLV brachytherapy (P < .0001)., Conclusions: PLV brachytherapy is as effective as FLV brachytherapy in reducing local recurrence and causes a significantly lower incidence of acute and late toxicities. The results of this study caution radiation oncologists regarding the careful use of FLV brachytherapy in patients with endometrial cancer and high-risk features., Competing Interests: Disclosures The work of all the listed parties was completed while they were affiliated with Weill Medical College of Cornell University, New York, New York; however, current affiliations are listed., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Cervical endometriosis is an uncommon form of endometriosis that is frequently diagnosed incidentally during histopathological evaluation of a hysterectomy or cervical biopsy specimens. Although some cases may be asymptomatic, the symptoms in some patients range from life-threatening hemorrhage to severe chronic pelvic pain. In asymptomatic patients, no further intervention might be required apart from observation and follow-up; however, patients with significant symptoms will require surgery. Primary cervical endometriosis is defined as presence of endometrial tissue on the anterior lip of the cervix, limited to the cervix surface and not extending below the squamous epithelium. Secondary cervical endometriosis is more common than the primary type and describes the disease extensions from the pelvis, or usually the rectovaginal septum. Superficial endometriosis is usually diagnosed by fine-needle aspiration, colposcopy, and cervical biopsy after a routine cervical smear, as endometrial cells detected during a PAP smear may be mistakenly removed as atypical glandular cells. Deep endometriosis may cause pelvic pain, vaginal bleeding, and spotting. In this case report, we present a rare case of cervical endometriosis, characterized by pelvic pain and menstrual irregularity, with endometrioma and adenomyosis, confirmed by histopathological evaluation of the specimen. A summary of the cervical endometriosis cases overview has been made to describe the changing clinical landscape of this rare condition., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Background: This study aimed to report clinical practice patterns of postoperative radiotherapy for stage I to II endometrial carcinoma (EC) patients treated in 13 Chinese medical centers., Methods: We included early stage EC patients treated by hysterectomy and adjuvant RT between 2003 and 2017 from 13 institutions. Patients were classified into 4 risk groups based on ESMO-ESGO-ESTRO recommendations (2014)., Results: A total of 1,227 cases were analyzed. Along the 15 years of the study, an increasing tendency was found towards administration for vaginal brachytherapy (VBT) alone, while the proportion of external beam pelvic radiotherapy (EBRT) alone remained stable in the corresponding period. When radiation modalities were stratified by risk groups, proportion of VBT alone significantly increased in all risk groups. The higher the risk, the later VBT became the main adjuvant treatment modality. However, EBRT alone or with VBT remained the main adjuvant method for high-risk patients. There were 13 dose-fractionation schemes for VBT alone with the scheme of 30 Gy in 6 fractions prescribed at 0.5cm under the vaginal mucosa accounting for most. There were 17 schemes for VBT boost and the most common schedule was 10 Gy in 2 fractions. The upper 3-5cm part of vagina was the most frequent target. 89.6% of the practitioners performed two-dimensional VBT technique. The median dose for EBRT was 50 Gy. From 2003 to 2017, conventional radiotherapy was gradually replaced by three-dimensional conformal radiotherapy modality and intensity modulated radiotherapy., Conclusion: We report a significant shift from EBRT to VBT alone for high-intermediate-risk, intermediate-risk and low-risk EC patients from 2003 to 2017 while EBRT remained the main radiation modality for high-risk early stage patients. There has been remarkable heterogeneity among VBT dose fractionation schedules across China., Trial Registration: The clinical trial ID was ChiCTR-PRC-17010712. It was authorized by the Institutional Review Board of Peking Union Medical College Hospital (N0. S-K139)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To develop a model to identify women likely to be severely impacted by vulvovaginal atrophy (VVA), based on their experience of symptoms and non-clinical factors., Methods: Multivariate statistics and machine-learning algorithms were used to develop models using data from a cross-sectional, observational, multinational European survey. A set of independent variables were chosen to assess subjective VVA severity and its impact on daily activities., Results: A final composite model was selected that included three categories of variables: clinical severity, patient demographics/clinical characteristics and Day-to-Day Impact of Vaginal Aging (DIVA) variables related to emotion/mood, impact on lifestyle and frequency of sex. The model accurately classified 71% of women. Three DIVA variables (feeling bad about yourself, desire/interest in sex, physical comfort related to sitting) explained much of the variation in the dependent variable of the model. Over 90% of the impact of VVA relates to certain psychosocial and behavioral aspects that can be identified without the need to consider physical signs/symptoms., Conclusion: Non-clinical factors can contribute significantly to the overall VVA burden.Questions used in developing the composite model could form the basis of an instrument to help screen women prior to clinical consultation and improve VVA management.

Competing Interests: Financial disclosure/conflicts of interest: A.L.C. has received past funding from Butler Snow LLC and MsMedicine Provider Executive Group, receives current funding from Hart Wagner LLC, and receives ongoing funding from Astellas.

It is estimated that the 25-50% of women who are reaching menopause every year report symptoms related to the genitourinary syndrome of menopause (GSM). The symptoms are not due simply to lack of estrogen. One possible contributing cause of symptoms is the vaginal microbiota. The vaginal microbiota is a dynamic entity and plays a critical role in the pathogenic interplay of postmenopausal changes. Treatment of this syndrome depends on the severity and type of the symptoms and on the preferences and expectations of women. As there are many treatment options, therapy should be individualized. While new evidence on the role of Lactobacilli in premenopause is emerging, the role of Lactobacilli is still unclear in GSM and the impact of microbiota on vaginal health remains conflictual. However, some reports show promising data on the effect of probiotic therapy in menopause. In the literature there are few studies and small population samples on the role of an exclusive therapy with Lactobacilli and further data will be mandatory. Studies involving large numbers of patients and different intervention periods will be necessary to obtain evidence of the preventive and curative role of vaginal probiotics.

The vagina is traditionally thought of as a passive organ in the female reproductive system, serving primarily as a passageway for menstrual blood, sexual intercourse and childbirth. However, recent research has shed light on the vagina's role as an endocrine organ that plays a crucial role in female hormonal balance and overall health. Particularly, growing evidence shows that the human vagina can be considered both as source and target of androgens, in view of the novel concept of 'intracrinology'. Besides the well-known role of estrogens, androgens are also crucial for the development and maintenance of healthy genitourinary tissues in women. As androgen levels decline with age, and estrogen levels fall during the menopausal transition, the tissues in the vagina, together with those in the urinary tract, become thinner, drier and less elastic, leading to a variety of uncomfortable and sometimes painful symptoms, clustered in the genitourinary syndrome of menopause (GSM). Given the lack of testosterone-based or androstenedione-based products approved by regulatory agencies to treat GSM, the possibility of using intravaginal prasterone, which works by providing a local source of dehydroepiandrosterone (DHEA) to the vaginal tissues, appears to be a targeted treatment. Further studies are needed to better assess its safety and efficacy.

Competing Interests: Financial disclosure/conflicts of interest: None reported.

Vulvovaginal atrophy (VVA) is a chronic progressive condition that involves the genital and lower urinary tracts, related to the decrease of serum estrogenic levels when menopause occurs. The definition of genitourinary syndrome of menopause (GSM) is a medically more accurate, all-encompassing and publicly acceptable term than VVA. Due to the chronic progressive trend of GSM, symptoms tend to reappear after the cessation of therapy, and frequently long-term treatment is required. First-line therapies include vulvar and vaginal lubricant or moisturizers, and, in the case of failure, low-dose vaginal estrogens are the preferred pharmacological therapy. Populations of patients, such as breast cancer (BC) survivors, are affected by iatrogenic GSM symptoms with concerns about the use of hormonal therapies. The non-ablative erbium:YAG laser and the fractional microablative CO 2 vaginal laser are the two main lasers evaluated for GSM treatment. The aim of this comprehensive review is to report the efficacy and safety of Er:YAG and CO 2 vaginal lasers for GSM treatment. Vaginal laser therapy has been demonstrated to be effective in restoring vaginal health, improving VVA symptoms and sexual function. The data suggest that both Er:YAG and CO 2 vaginal lasers are safe energy-based therapeutic options for management of VVA and/or GSM symptoms in postmenopausal women and BC survivors.

Local estrogen therapy (LET) is the mainstay of treatment for vaginal dryness, dyspareunia and other urogenital symptoms because it may reverse some pathophysiological mechanisms associated with decreasing endocrine function and increasing aging. Over the years, several vaginal products including different formulations (tablets, rings, capsules, pessaries, creams, gels and ovules) and molecules (estradiol [E2], estriol [E3], promestriene, conjugated equine estrogens and estrone) have been used with superimposable therapeutic results. Low-dose and ultra-low-dose LET is the gold standard due to its minimal systemic absorption, with circulating E2 levels persistently remaining in the postmenopausal range. In healthy postmenopausal women, preference among the various products is presently the main driver and dissatisfaction with LET seems high, namely because of the delayed use in those with severe symptoms of genitourinary syndrome of menopause (GSM). Specific concerns remain in high-risk populations such as breast cancer survivors (BCS), especially those under treatment with aromatase inhibitors. Based on the multitude of symptoms under the umbrella of GSM definition, which includes vulvovaginal atrophy (VVA), it is mandatory to investigate specific effects of LET on quality of life, sexual function and genitourinary conditions by conducting studies with a patient-tailored focus.

Genitourinary syndrome of menopause (GSM) is caused by chronic deprivation of estrogen and other sex steroids during the postmenopausal period, which leads to changes in the vulvovaginal tissues. These changes cause bothersome symptoms, such as vaginal dryness, pruritus, dyspareunia, increased daytime urinary frequency, urgency and urinary incontinence, which have considerable negative effects on women's quality of life and sexual function. Recent studies have investigated a novel treatment approach for GSM. Pelvic floor muscle (PFM) rehabilitation, a low-cost conservative management with no side-effects, has been studied alone or in combination with other treatment modalities to reduce the signs and symptoms of GSM. The aim of this article is to discuss why PFM rehabilitation could be useful for women with GSM, how it may help improve signs and symptoms of GSM and when this treatment should be recommended.

Vulvovaginal atrophy (VVA) is an underdiagnosed and undertreated chronic condition resulting in physiological and histological changes in the genitourinary tract of postmenopausal women. Treatment of moderate to severe VVA includes local estrogens, dehydroepiandrosterone (DHEA) and oral ospemifene, a third-generation selective estrogen receptor modulator (SERM). Due to venous thromboembolism (VTE) safety concerns classically associated with the SERM class, and as part of its original marketing authorization approval (MAA), the European Medicines Agency (EMA) requested the performance of a 5-year post-authorization safety study (PASS) to study the incidence rate of VTE among women receiving ospemifene. The results have led to important regulatory changes to ospemifene's labeling, extending its indication and eliminating concerted risk management measures. A panel of experts discussed and reached consensus on the impact of these regulatory changes on clinical practice, reflecting on the reassurance of ospemifene's benefit-risk balance and recommending its positioning as a first-line pharmacological treatment option for moderate to severe VVA together with local therapies. In a scenario where different treatments present similar efficacy and safety profiles, a shared decision between clinician and patient, according to her needs and preferences over time, is fundamental to improve adherence and persistence with sequential treatment, contributing to the achievement of health outcomes.

Many breast cancer survivors (BCS) suffer the consequences of antineoplastic treatments that induce a hypoestrogenic state, leading to chronic climacteric symptoms such as genitourinary syndrome of menopause (GSM), arousing significant alteration in their quality of life. Non-hormonal therapies (NHT) are first-line treatments, safe but with mild efficacy. When facing moderate-severe GSM, the options for BCS are limited: local estrogen therapy, considered the 'gold standard' but with concerns about safety; vaginal androgens and prasterone, which seem to trigger an activation of estrogen and androgen receptors of the vaginal epithelium layers, without activating estrogen receptors on other tissues, being potentially safe but still without strong evidence in favor of BCS; vaginal lasers, which appear to improve vascularization of vaginal mucosa by stimulating the remodeling of the underlying connective tissue, but with contradictory results of efficacy in recent randomized clinical trials; and ospemifene, an oral selective estrogen receptor modulator presenting mild vaginal estrogenic potency and anti-estrogenic effect at the endometrial and breast level, but still not recommended for use in BCS in recent North American Menopause Society guidelines. There is a need for further studies evaluating objectively the efficacy and safety of these promising therapeutic options. On the other hand, sexuality must be seen as a multifactorial issue, where GSM is only part of the problem; evidence shows that sexual counseling improves the quality of life of BCS. Finally, there is a need to limit the underdiagnosis and undertreatment of GSM in BCS; the primary goal of physicians treating BCS regarding this issue has to be the provision of information of what to expect regarding genital and sexual symptoms to BCS and to counsel on early first-line treatments that may help prevent more severe GSM.

Vulvovaginal atrophy (VVA) is a chronic and progressive disease that affects sexuality and quality of life. VVA is preventable and treatable, but requires long-term and often sequential treatment. Sequential treatment consists of designing a strategy that uses one or more medications for a long enough time to achieve the desired benefits with minimal risk and maximum adherence. Currently available therapeutic options consist of topical over-the-counter products (including non-hormonal lubricants and moisturizers applied to the vagina), systemic hormone therapy and estrogens, and prescribed vaginal dehydroepiandrosterone (DHEA). In addition, we have a selective estrogen receptor modulator, ospemifene, and new energy-based treatments (laser and radiofrequency). There are clear differences between the treatments both in the mechanism of action and in the efficacy. Compliance is very low, and patients complain about the use of the vaginal route, often due to its low efficacy, or express fear of the long-term use of estrogens or the price of the treatments. We believe that, as a first option, and for physiological, preventive and efficacy reasons, we should consider the prescription of treatments that work on estrogen receptors. As a second option, there are vaginal moisturizers, which are effective on symptoms but do not prevent or improve conditions. Finally, techniques using heat, which although each time represent a clearer alternative, but on the other hand are the cost and the long-term safety data, give us a third option. Of course, we consider that vulvar moisturizers and lubricants can be used at any time.

Malignant vulvar melanoma (VuM) and vaginal melanoma (VaM) represent a unique subgroup of rare malignant melanomas with critical biological properties that differ from other cancers. In Japan, adequate surveys have yet to be conducted. This study aimed to elucidate the clinicopathological demographics and outcomes of VuM and VaM in Japan. This retrospective observational study included women with invasive VuM or VaM identified from older medical records in Japan. We collected clinical data and used the Kaplan-Meier method to analyze progression-free survival (PFS) and overall survival (OS). Univariate and multivariate regression models were used to identify factors significantly related to survival. We identified 217 patients, 109 (50.2%) with VuM and 108 (49.8%) with VaM. The median PFS was 16.8 months in patients with VuM [95% confidence interval (CI), 23.1-87.7] and 15.6 months in those with VaM (95% CI, 8.4-12.6). The median OS was 43.9 months (95% CI, 60-138) and 31.1 months (95% CI, 24.8-45.3) in patients with VuM and VaM, respectively. Multivariate analysis showed that a disease stage higher than stage III, based on the American Joint Committee on Cancer (AJCC) guidelines, was associated with poorer PFS [hazard ratio (HR), 2.063; 95% CI, 0.995-4.278] and an unknown surgical margin was the only independent factor influencing OS (HR, 2.188; 95% CI, 1.203-3.977). The overall outcomes of invasive VuM and VaM in Japan remain poor. AJCC staging and surgical margins were significant predictors of survival., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Genitourinary syndrome of menopause (GSM) has a variety of effects on the urinary system and is an important consideration in the care provided to perimenopausal and postmenopausal patients when addressing urinary pathology. Here we discuss the common pathologies of the urinary system related to GSM including lower urinary tract symptoms and recurrent urinary tract infections. Female sexual dysfunction is not to be excluded as a critical part of a urologist's management of GSM but will be discussed elsewhere in this issue.

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., Competing Interests: Financial disclosure/conflicts of interest: C.B. is a partner at PeriPharm, Inc, and A.C. and C.R. are employees at PeriPharm, Inc, a company that has served as a consultant to Duchesnay, Inc, and has received funding from Duchesnay, Inc. A.F. and D.B. have served as consultants for Duchesnay, Inc. D.B. currently receives funding from AbbVie, Bayer, BioSyent, Duchesnay, Merck, Organon, Pfizer, and Searchlight. R.M. is an employee at Duchesnay, Inc. J.A.S. receives grant/research support from the following: AbbVie, Bayer Healthcare, Dare Bioscience, Enteris BioPharma, Mylan/Viatris, Myovant Sciences, ObsEva, and Viveve Medical; is on consulting/advisory boards of the following: Bayer Healthcare, Besins Healthcare, California Institute of Integral Studies (CIIS), Dare Bioscience, DEKA M.E.L.A S.r.l., Duchesnay, Inc, Femasys, KaNDy/NeRRe Therapeutics, Khyria, Madorra, Mitsubishi Tanabe Pharma Development America, QUE Oncology, Scynexis, Inc, Sprout Pharmaceuticals, Vella Bioscience; serves on the speaker's bureaus of the following: Mayne Pharma, Myovant Sciences, Pfizer, Pharmavite, Scynexis, and TherapeuticsMD; and is a stockholder (direct purchase) in Sermonix Pharmaceuticals., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Objective: The aim of the study is to describe the location, severity, and frequency of genitourinary symptoms in postmenopausal women enrolled in a randomized trial of treatment for vulvovaginal discomfort., Methods: This is a post hoc analysis of enrollment responses for participants in the MsFLASH Vaginal Health Trial. Participants were asked about the severity (0-3), frequency (in days per week) and location (vulvar or vaginal) of itch, dryness, pain/soreness, irritation, as well as severity and frequency of pain with penetration, vaginal discharge, urinary incontinence, and urinary urgency., Results: A total of 302 participants were enrolled, with a mean age of 60.9 ± 4.1 years. The mean number of moderate-severe vulvovaginal symptoms experienced by trial participants in the month before enrollment was 3.4 ± 1.5, with a range from 1 to 7. The most commonly reported symptom across all severity categories was vaginal dryness (285/302, 94%), but the one most frequently rated as severe was pain with vaginal penetration (121/302, 40%). Vaginal dryness was the symptom with highest frequency; 53% of participants with that symptom reported experiencing it ≥4 d/wk. For vaginal symptoms, 80% of participants (241/302) reported that at least one of these symptoms occurred during or after sex while only 43% (158/302) reported that at least one vulvar symptom occurred during or after sex. Urinary incontinence (202/302, 67%) and urinary frequency (128/302, 43%) were the two most commonly reported urinary issues., Conclusions: Our data highlight the complexity of genitourinary syndrome of menopause symptoms in quantity, severity, and frequency, suggesting that measuring distress, bother, or interference may be the most comprehensive measure., Competing Interests: Financial disclosure/conflicts of interest: C.M.M. reports receiving grant funding from Scynexis, Inc, and has served as a consultant to Scynexis, Inc, Ferring Pharmaceuticals. S.D.R. receives research funding from Bayer, ongoing funding from UpToDate, and additional funding from the National Institutes of Health. The other authors have nothing to disclose., (Copyright © 2023 by The North American Menopause Society.)

The demand for non-hormonal therapies for vulvovaginal atrophy (VVA) is increasing due to an increasing number of patients surviving long term post cancer diagnosis, as well as increased public knowledge of the symptoms of menopause and availability of non-hormonal therapies. Treatment options are wide-ranging and encompass different formulations and methods of application. This review summarizes the key characteristics of the main forms of these therapies, as well as considering the current evidence for each of them and where future clinical studies should be directed. Care for VVA may be in primary care, or under gynecology or oncology. Further research requirements include the need for long-term data as well larger randomized controlled trials into alternatives where vaginal estrogen cannot be used as first-line treatment. Widespread education of health-care providers and patients on VVA and the impact on quality of life is urgently needed, as well as increased use of non-hormonal methods in routine clinical practice.

Background: The term genitourinary syndrome of menopause was first used in 2014 by the North American Menopause Society and the International Society for the Study of Women's Sexual Health to describe conditions previously known as atrophic vaginitis, urogenital atrophy, or vulvovaginal atrophy. It is a complex, chronic, progressive condition characterized by a wide range of signs and symptoms affecting sexual function and the tissues of the urinary and genital tracts. The main cause of genitourinary syndrome of menopause is estrogen deficiency caused by ovarian removal or dysfunction. The most bothersome symptoms are vaginal dryness, decreased vaginal lubrication, and pain during penetration and intercourse. They all have a negative impact on the quality of life., Conclusions: The main goal of treatment is to relieve the symptoms. Treatment modalities are pharmacological or non-pharmacological. The first-line treatment for mild to moderate symptoms is the use of personal lubricants and moisturizers, but the gold standard is estrogen replacement therapy. Hormone therapy may not be an option for women with hormone-dependent cancer., (© 2023 Nina Kovacevic et al., published by Sciendo.)

Background: Vulvovaginal laxity, atrophic vaginitis, and orgasmic dysfunction are not only aesthetic but also sexual problems. Autologous fat grafting (AFG) facilitates tissue rejuvenation through the effects of adipose-derived stem cells; the fat grafts serve as soft-tissue filler. However, few studies have reported the clinical outcomes of patients undergoing vulvovaginal AFG., Objectives: The aim of this study was to describe a new technique, micro-autologous fat transplantation (MAFT), for AFG in the vulvovaginal area. Posttreatment histologic changes in the vaginal canal that imply improved sexual function were assessed., Methods: This retrospective study enrolled females who underwent vulvovaginal AFG performed through MAFT between June 2017 and 2020. Assessments were based on the Female Sexual Function Index (FSFI) questionnaire and on histologic and immunohistochemical staining., Results: In total, 20 female patients (mean age, 38.1 years) were included. On average, 21.9 mL of fat was injected into the vagina and 20.8 mL in the vulva and mons pubis area. Six months afterwards, the patients' mean total FSFI score (68.6) was significantly higher than that at baseline (43.8; P < .001). Histologic and immunohistochemical staining of vaginal tissues revealed substantially increased levels of neocollagenesis, neoangiogenesis, and estrogen receptors. By contrast, the level of protein gene product 9.5, which is associated with neuropathic pain, was considerably lower after AFG., Conclusions: AFG performed through MAFT in the vulvovaginal area may help manage sexual function-related problems in females. In addition, this technique improves aesthetics, restores tissue volume, alleviates dyspareunia with lubrication, and reduces scar tissue pain., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To study the clinical, cytological, and vaginal microbiota findings in patients with Mayer-Rokitansky-Küster-Hauser syndrome who underwent neovaginoplasty using Nile tilapia fish skin., Methods: This is a cross-sectional study with 7 cisgender women with Mayer-Rokitansky-Küster-Hauser syndrome who had previously undergone neovagina reconstruction using Nile tilapia fish skin at a university hospital. Local institutional review board approval and written permission from the patient were obtained. Between August 2019 and November 2021, within 12 to 24 months after surgery, vaginal specimens were obtained for conventional oncotic and hormonal cytology, and for Gram staining. The Nugent scores were calculated. Colposcopy was also performed., Results: Squamous cells without atypia were found in all patients. Five patients had intermediate vaginal microbiota (Nugent score of 4), which was determined by the presence of few lactobacilli on Gram staining. In hormonal cytology, 4 patients presented with findings compatible with menacme. No colposcopic change was observed. When postsurgical dilation was performed correctly, a mean vaginal length of 8.3 cm was maintained after 1 year of follow-up., Conclusions: Squamous cells without atypia were present in neovaginas with Nile tilapia fish skin. Most vaginal contents revealed intermediate microbiota and hormonal results compatible with menacme. Studies with a greater number of patients are necessary for a more comprehensive understanding of the microbiome in neovaginas with this new technique, thereby providing support for the treatment and prevention of associated pathologies., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2023, ASCCP.)

Purpose: The main aim of this study was to investigate the long-term risk of disease recurrence in women treated for high-grade vaginal intraepithelial neoplasia (HG-VaIN)., Methods: We conducted a retrospective analysis on a cohort of 82 women diagnosed with HG-VaIN between 2010 and 2021 at the "Regional Referral Center for Prevention, Diagnosis and Treatment of HPV-related Genital Disorders", Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. All women underwent either ablative treatment (CO 2 laser ablation or electrocoagulation) or cold-knife excision., Results: In our series, the recurrence rate following treatment was 17%. The 5-year cumulative probability of recurrence was 30.4% and the median time to recurrence was 15.5 months. None of the patients progressed to invasive vaginal cancer during follow-up. A concomitant cervical or vulvar intraepithelial lesion was significatively associated with an increased risk of recurrence (p = 0.006)., Conclusions: The results of our study suggest that women with HG-VaIN are at high risk of developing disease recurrence after treatment, especially patients with a concomitant cervical or vulvar intraepithelial lesion. In these women strict monitoring is mandatory to obtain an early identification of recurrence., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Lasers and energy-based technologies have been developed for genitourinary applications over the past several decades., Aims: This consensus article aims to categorize the published articles and clinical trial data that culminated in protocol development of technology for genitourinary applications, and to develop consistent parameters in future clinical trials., Materials and Methods: The published articles and clinical trials data on lasers and energy-based devices applied to genitourinary conditions were categorized according to device and condition and consensus developed on protocols and parameters., Results: The devices in genitourinary applications were classified as fractional lasers, radiofrequency and high-intensity focused electromagnetic field therapy. The consensus of the protocols and parameters based upon the published clinical trials of their application to the vaginal and urologic conditions associated with genitourinary syndrome of menopause was developed and organized according to device and condition., Discussion: The status of FDA clearances and future pathways are discussed., Conclusions: This consensus article categorizes and presents the protocols and practices for the main classes of lasers and energy-based devices for genitourinary applications in future clinical trials., (© 2023 Wiley Periodicals LLC.)

Under 10% of gynaecological cancers are diagnosed in the vulva and vagina, mostly squamous cell carcinomas. Melanoma, Paget disease, basal cell carcinomas, and other cancers can present with vulval/vaginal symptoms. The pathology information system of a tertiary referral center for vulvo-vaginal cancers was searched for cancers of the vulva and vagina from 1996 to 2019. Squamous carcinomas were excluded, and the remaining entities were catalogued. A total of 221 nonsquamous cancers were found, including 135 vaginal and 86 vulval cases. One hundred eight cases of metastatic carcinomas from the endometrium, cervix, ovary, bowel, bladder, kidney, and breast formed the largest category. Basal cell carcinomas constituted the second largest category. Others included melanomas, Paget disease, and adenoid cystic carcinomas. Primary adenocarcinomas included porocarcinoma, mammary type carcinoma, enteric type carcinoma, clear cell carcinoma, Bartholin gland adenocarcinoma and malignant transformation of hidradenoma papilliferum. The vulva and vagina can harbor a wide range of nonsquamous malignancies. The most challenging of these are adenocarcinomas which can be metastatic from other sites. The dominance of metastatic carcinomas in this series is likely to reflect consultation practice of specialist pathologists., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Abstract: It is estimated that up to 50% to 90% of postmenopausal women may experience genitourinary syndrome of menopause (GSM), which may have a detrimental impact on quality of life. One of the most effective modes of treatment of GSM is low-dose vaginal estrogens. Numerous studies have addressed the safety of these estrogens using endometrial biopsy and/or endometrial thickness on ultrasound. Based on these studies, the consensus is that low-dose vaginal estrogens do not substantially increase the risk of endometrial hyperplasia or cancer; however, the data are severely limited by short duration of follow-up. Although long-term trials are warranted, they are difficult to carry out, costly, and will not yield data for years. More immediate information regarding endometrial safety may be obtained from studies measuring endometrial tissue and serum concentrations of estradiol, estrone, and relevant equine estrogens after administration of different estrogen formulations and doses. This would allow us to understand better the metabolism of estrogens by the vagina and endometrium, and how much estrogen is reaching the endometrium. Here, we discuss metabolism, receptor binding, and signaling of estrogens in vaginal and endometrial tissue, and summarize the existing studies on the endometrial impact of low-dose vaginal estrogen treatment in postmenopausal women., Competing Interests: Financial disclosures/conflicts of interest: M.ES. received research support from Exact Sciences related to studies of gynecologic cancer detection, tangentially related to this work. The other authors have nothing to disclose., (Copyright © 2023 by The North American Menopause Society.)

Objective: To assess the correlation of different vulvovaginal atrophy therapeutic options with the quality of life of postmenopausal women., Study Design: The CRETA study is a descriptive, observational, cross-sectional, multicenter study designed to measure, besides treatment satisfaction and adherence, the quality of life of postmenopausal women diagnosed with vulvovaginal atrophy in 29 hospitals and centers across Spain., Main Outcome Measures: The study enrolled postmenopausal women currently receiving treatment with vaginal moisturizers, local estrogen therapy or ospemifene. Clinical features and treatment perceptions were collected by self-report questionnaire and quality of life was evaluated using the Cervantes scale., Results: Among the 752 women included, the ospemifene cohort showed a statistically significant lower global score (44.9 ± 21.7) on the Cervantes scale (and therefore, a better quality of life) than the cohorts treated with moisturizers (52.5 ± 21.6, p = 0.003) or local estrogen therapy (49.2 ± 23.8, p = 0.0473). In the analysis by domains, ospemifene-treated women showed statistically significant better scores in menopause & health and psychological status than moisturizers-treated women (p < 0.05). In the domains of sexuality and couple relations, the score for the quality of life of the ospemifene cohort was statistically significantly better than the scores in either of the cohorts treated with moisturizers (p < 0.001) or local estrogen therapy (p < 0.05)., Conclusions: Postmenopausal women diagnosed with vulvovaginal atrophy and treated with ospemifene have better quality of life than women treated with vaginal moisturizers or local estrogen therapy. The improvement observed with ospemifene is more remarkable in those aspects related to sex life and couple relations. CLINCIALTRIALS., Gov Number: NCT04607707., Competing Interests: Declaration of competing interest Shionogi S.L.U. sponsored the study and provided support for the medical writing assistance by Kalispera medical writing S.L. RS-B has received consulting fees and speaker's honoraria from Shionogi. SP has received consulting fees and speaker's honoraria from Shionogi and Bayer HC, Exeltis, Gedeon Richter, NovoNordisk, Procare H, Serelys, Lacer, Sandoz, Pfizer, Theramex. MJC has received consulting fees and speaker's honoraria from Shionogi. JGC and JJQM are currently working at Shionogi S.L.U. The other authors declare that they have no competing interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance and Objectives: Evaluation and treatment of dyspareunia remains a significant unmet need despite the availability of safe and effective treatments. The objectives of this review are to consider evaluation techniques, the medical causes, and treatment options for dyspareunia in postmenopausal women., Methods: This narrative review used PubMed to search for English-language articles related to postmenopausal dyspareunia. Search terms included, but were not limited to, dyspareunia, genitourinary syndrome of menopause, sexual dysfunction, postmenopausal dyspareunia, posthysterectomy dyspareunia, and postcancer dyspareunia., Findings: Many postmenopausal women with dyspareunia do not discuss their symptoms with their physicians. Healthcare clinicians should broach the topic of dyspareunia with their patients using oral or written questionnaires. In addition to a thorough medical history and physical examination, various tools can be used as further assessments, including vaginal pH, vaginal dilators, imaging, vulvar biopsy, vulvoscopy and photography, the cotton swab test, sexually transmitted infection screening, and vaginitis testing. Although dyspareunia in postmenopausal women is often due to the genitourinary syndrome of menopause, other conditions can also cause dyspareunia, including hypertonic pelvic floor, hysterectomy, cancer treatment, lichen conditions, vulvar cancer, vestibulodynia, and pelvic organ prolapse. Some of the treatments discussed include lubricants, moisturizers, vaginal estrogen, ospemifene, dehydroepiandrosterone, local testosterone therapy, cannabidiol, and fractional CO 2 laser treatments. In some cases, dyspareunia may need to be specifically addressed by pelvic floor physical or sex therapists., Conclusions: Dyspareunia is a common issue in postmenopausal women, which remains largely untreated. Women with dyspareunia require a thorough history, targeted physical examination, and coordination of multiple disciplines including medical clinicians, pelvic floor physical therapists, and sex therapists., Competing Interests: Financial disclosure/conflicts of interest: L.F.S. received a consultant fee for advisory board participation from Astellas Pharma, Inc, and is a shareholder in Sermonix., (Copyright © 2023 by The North American Menopause Society.)

Purpose: Analyse the impact of different prognostic factors on G2-late vaginal complications after vaginal brachytherapy (VBT) ± external beam radiotherapy (EBRT) in postoperative endometrial cancer (PEC)., Methods: One hundred and twenty-six PEC patients treated with VBT ± EBRT were retrospectively analysed considering age, body mass index, applicator diameter, clinical target volume (CTV), use of dilators, chemotherapy and EQD2 (α/β=3) at the most exposed 2 cm 3 of the CTV as prognostic factors for vaginal complications. Late vaginal complications were evaluated using objective LENT-SOMA criteria., Statistics: descriptive analysis, Chi-square, Fisher and Student tests were applied. Univariate and multivariate analyses were performed with the Baptista-Pike exact method and multiple logistic regression., Results: Mean age was 65 years (SD ± 10), and median follow-up was 66 months (8-104). 19/126 patients (15%) showed G2-late vaginal complications, and 107/126 (85%) G0-G1. Univariate analysis showed: CTV ≤ 9 cm 3 (p = 0.036), use of dilators < 9 months (p = 0.015), and total ≥ 68 Gy EQD2 received by 2 cm 3 of CTV (p = 0.039) were associated with G2-late vaginal toxicity. Multivariate analysis showed the use of dilators < 9 months as an independent prognostic factor for G2-late vaginal toxicity (p = 0.043, OR 8.59, CI 1.59-159.9)., Conclusion: The use of dilators < 9 months in VBT ± EBRT for PEC was an independent prognostic factor for G2-late vaginal toxicity. The use of vaginal dilators ≥ 9 months requires further analysis in studies evaluating late vaginal toxicity., (© 2023. The Author(s).)

Background: Endometriosis is a clinical condition associated with genetic, endocrine, and immunological factors, present in 6 to 10% of women of reproductive age. Currently, the human microbiota has been studied and associated with the evolution of diseases due to its influence on pathogenesis, indicating that changes in the colonization of microorganisms in the genitourinary and gastrointestinal systems can promote physiological changes that can trigger inflammatory and immunological processes and hormonal dysregulation, which can be linked to endometriosis. Thus, this systematic review and meta-analysis evaluated microbiota changes in women with endometriosis., Methods: The following electronic databases were searched up to April 2022: Medline, Embase, Web of Science, Cochrane Library, and gray literature (Google Scholar), using the keywords "dysbiosis", "microbiome" and "endometriosis", combined with their synonyms. The observational studies conducted with women diagnosed with endometriosis and women without endometriosis as controls were included. For the analyses, a standard mean difference with a 95% confidence interval was used using RevMan software (version 5.4), and for methodological quality assessment, the Newcastle-Ottawa scale was used., Results: A total of 16 studies were found in the literature assessing the composition of the microbiota in women with endometriosis, and no significant difference were found for changes in alpha diversity analysis in gut microbiota (SMD = -0.28; 95% CI = -0.70 to 0.14; P = 0.19; I 2 = 52%; four studies, 357 participants) or vaginal microbiota (SMD = -0.68; 95% CI = -1.72 to 0.35; P = 0.19; I 2 = 66%; two studies, 49 participants)., Conclusion: In intestinal and vaginal samples from women with endometriosis, alpha-diversity did not present a significant difference when compared to the control population. However, each study individually showed a possible relationship between the female microbiota and endometriosis. This trial is registered with CRD42021260972., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Tamy Colonetti et al.)

Study Objective: Deep endometriotic lesions may involve the deep parametrium, which is highly vascular and includes numerous somatic and autonomous nerves [1,2]. Surgeons who dissect in this area must always be prepared to deal with major bleeding and to master the different techniques of hemostasis. The goal of this video is to show the steps of laparoscopic excision of deep endometriotic lesion of the parametrium and the steps taken to control the bleeding encountered from one of the venous branches., Design: Surgical educational video., Setting: Endometriosis referral center., Interventions: Excision of the endometriotic parametrial nodule and the release of the sacral plexus, with excision of the vaginal involvement, rectal disc excision, and segmental resection of the sigmoid colon. The video shows the excision of a deep endometriosis involving the right parametrium, mid rectum, sigmoid colon, and vagina. The excision of deep endometriosis of the parametrium followed the 10 steps previously described [1]. During this procedure, careful dissection of arteries and veins branching from the internal iliac vessels is a crucial step. However, injury of one or more of the vessels can still occur. The video presents the different techniques used to control the bleeding from a venous injury faced during the dissection around the nodule in the parametrium, including energy use, clips, hem-o-loks, and direct continuous pressure. Of note, hemostatic agents are available; however, we have not yet successfully used them in the circumstances in which large veins were injured. The ultimate solution in our case was the clamping of the injured vessels, allowing meticulous dissection and sectioning of all the feeding vessels, while taking care not to injure the sacral roots that were just beneath these veins. Total operative time was 4 hours., Conclusion: Surgery of deep endometriosis involving the sacral plexus may be successfully done laparoscopically. Thorough knowledge of the deep pelvis anatomy is mandatory, and the surgeon should master various techniques of hemostasis, particularly on deep veins., (Copyright © 2023 AAGL. Published by Elsevier Inc. All rights reserved.)

Malignant mesenchymal tumors of the female genital tract are uncommon gynecological cancers, particularly in the vagina. They are typically aggressive and often relapse, both locally and at distant sites. The treatment of choice for primary tumors is surgical excision as they are generally refractory to chemotherapy and radiotherapy. We describe the case of a vaginal leiomyosarcoma in a 43-year-old woman who presented with abnormal genital bleeding and discharge. The tumor was excised but recurred locally after just 11 months. It was removed by hysterectomy with double adnexectomy and partial vaginal excision., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To determine and compare the value of magnetic resonance imaging (MRI) and transvaginal sonography (TVS) in the diagnosis of rectal endometriosis., Methods: In this cross-sectional study, 555 patients with rectal endometriosis, who had undergone MRI and TVS before laparoscopic operation, were included. The sensitivity, specificity, and accuracy of these two imaging modalities were evaluated and compared based on histopathologic reports and three different kinds of rectal endometriosis surgeries (shaving as a first group and disk and segmental resection methods combined as a second group)., Results: Sensitivity, specificity, accuracy, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of ultrasound in the diagnosis of rectal endometriosis were, respectively, 69.55% (65.4%-73.4%), 91.30% (72%-98.9%), 70.4% (66.4%-74.17%), 11.48% (9.77%-13.43%), 99.46% (98%-99.86%), 8.0 (2.12-30.1), and 0.3 (0.28-0.4). These values were 51.37% (47.1%-55.6%), 79.17% (57.8%-92.9%), 52.53% (48.3%-56.6%), 6.64% (5.39%-8.16%), 98.26% (96.26%-99.2%), 2.47 (1.13-5.4), and 0.6 (0.49-077) for MRI. Even though ultrasound had better accuracy for detection of superficial rectal endometriosis (Group 1) (P < 0.001), the sensitivity, specificity, and accuracy of both imaging modalities in diagnosis of deep rectal lesions (Group 2) were almost identical., Conclusion: TVS should be considered as a first-line modality for diagnosis of rectal endometriosis, mainly because of its greater availability, lower cost, and higher accuracy., (© 2022 International Federation of Gynecology and Obstetrics.)

Aim: There is need for a straightforward objective measure to evaluate vaginal wall changes related to hypoestrogenism. The aim of this pilot study was to evaluate a transvaginal ultrasound procedure for the quantification of vaginal wall thickness in order to differentiate between healthy premenopausal women and postmenopausal women with genitourinary syndrome of menopause using ultra-low-level estrogen status as a model., Methods: We performed a prospective, two-arm, cross-sectional pilot study comparing vaginal wall thickness measured by transvaginal ultrasound in postmenopausal breast cancer survivors using aromatase inhibitors with genitourinary syndrome of menopause (GSM group) and healthy premenopausal women (control or C group) from October 2020 to March 2022. After intravaginal introduction of 20 cm 3 of sonographic gel, vaginal wall thickness was measured by transvaginal ultrasound in the anterior, posterior, and right and left lateral walls (four quadrants). The study methods followed the STROBE checklist., Results: According to the results of a two-sided t-test, the mean vaginal wall thickness of the four quadrants in the GSM group was significantly less than that of the C group (2.25 mm vs 4.17 mm, respectively; p < 0.001). Likewise, the thickness of each of the vaginal walls (anterior, posterior, right and left lateral) statistically differed between the two groups (p < 0.001)., Conclusion: Transvaginal ultrasound with intravaginal gel may be a feasible objective technique to assess genitourinary syndrome of menopause, showing clear differences in vaginal wall thickness between breast cancer survivors using aromatase inhibitors and premenopausal women. Possible correlations with symptoms or treatment response should be assessed in future studies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: A phase 2 study showed that 15 mg estetrol (E4) alleviates vasomotor symptoms (VMS). Here, we present the effects of E4 15 mg on vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life., Methods: In a double-blind, placebo-controlled study, postmenopausal participants (n = 257, 40-65 y) were randomized to receive E4 2.5, 5, 10, or 15 mg or placebo once daily for 12 weeks. Outcomes were the vaginal maturation index and maturation value, genitourinary syndrome of menopause score, and the Menopause Rating Scale to assess health-related quality of life. We focused on E4 15 mg, the dose studied in ongoing phase 3 trials, and tested its effect versus placebo at 12 weeks using analysis of covariance., Results: Least square (LS) mean percentages of parabasal and intermediate cells decreased, whereas superficial cells increased across E4 doses; for E4 15 mg, the respective changes were -10.81% ( P = 0.0017), -20.96% ( P = 0.0037), and +34.17% ( P < 0.0001). E4 15 mg decreased LS mean intensity score for vaginal dryness and dyspareunia (-0.40, P = 0.03, and -0.47, P = 0.0006, respectively); symptom reporting decreased by 41% and 50%, respectively, and shifted to milder intensity categories. The overall Menopause Rating Scale score decreased with E4 15 mg (LS mean, -3.1; P = 0.069) and across doses was associated with a decreasing frequency and severity of VMS ( r = 0.34 and r = 0.31, P < 0.001)., Conclusions: E4 demonstrated estrogenic effects in the vagina and decreased signs of atrophy. E4 15 mg is a promising treatment option also for important menopausal symptoms other than VMS., Competing Interests: Financial disclosure/conflicts of interest: M.T. and M.J. are employees, U.G. and J.-M.F. are consultants, and W.H.U. and R.A.L. are members of the Scientific Advisory Board of Mithra Pharmaceuticals. W.H.U. received funding from Pharmavite, Los Angeles. H.J.T.C.B. is president and CEO of Pantarhei Bioscience., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Purpose: Endometrial Cancer (EC) is the most common gynecologic malignancy in the United States. Standard treatment is TAH/BSO with radiation therapy (RT) and chemotherapy given based on risk. Treatment can cause significant vaginal changes, including shortening, narrowing, loss of elasticity, atrophy, and dryness. These are not life threatening, but affect a woman's physical, psychological, and social functioning. Adjuvant vaginal dilator use is often advised, but there are inconsistent recommendations on use. This prospective study compared vaginal length changes and sexual function in women compliant with dilation versus not after surgery and RT., Methods and Materials: Enrolled patients underwent surgery for Stage I-IIIC EC ±RT. Vaginal dilator use was recommended for women receiving RT (external beam or brachytherapy). Vaginal length was measured with a vaginal sound and the Female Sexual Function Index (FSFI) was used to assess sexual function., Results: Forty-one enrolled patients had sufficient data for analysis. Dilation significantly increased FSFI scores (p = 0.02) while RT without dilation showed a significant decrease (p = 0.04). Dilation helped maintain vaginal length for all patients (0 cm vs. 1.8 cm loss (p = 0.03)). Individual arms did not show statistically significant changes in length with dilation, though the trend showed RT without dilation had an average loss of 2.3 cm as compared to only 0.2 cm for regular dilation. Notably, there was no difference in length change with dilation for surgery alone versus surgery and RT (p = 0.14)., Conclusion: This data provides novel, prospective evidence of the benefit of vaginal dilation for maintaining vaginal length and improving sexual health after any pelvic treatment for EC. This evidence also supports that the addition of RT after surgery does not appear to significantly worsen vaginal shortening. This study has important implications for providing a strong foundation for future studies and helping to establish solid clinical management criteria for the prevention of vaginal stenosis and promotion of female sexual health., (Copyright © 2023 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)