Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials.

OBJECTIVE: The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause. METHODS: Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test. RESULTS: The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo ( P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: -0.4 and -0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (-0.65, -0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (-39.9%, -34.9%) cells; study 2: most bothersome symptom (-0.4, -0.5), vaginal pH (-0.57, -0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (-34.1%, -33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%-23% vs 9%-11%). Serious adverse events were infrequent and no deaths occurred. CONCLUSIONS: In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.

Needs assessment of menopause education in United States obstetrics and gynecology residency training programs.

OBJECTIVE: This study aimed to assess the variance in menopause education, educational resources, and the needs of obstetrics and gynecology (ObGyn) residency programs by conducting a national survey of program directors (PDs). METHODS: In 2022, an institutional review board-approved Web-based Qualtrics survey was designed and distributed electronically to 145 US ObGyn residency PDs. The survey consists of 15 questions. The main outcomes are reported using descriptive statistics. RESULTS: The survey was completed by 99 of 145 PDs (68.3%). Almost all participants (92.9%) strongly agreed that residents nationwide should have access to a standardized menopause curriculum that could be utilized in their programs. Only 31.3% reported having a menopause curriculum in their residency program. Of the programs with a menopause curriculum, 96.8% reported using lectures, 77.4% reported assigned readings, and 74.2% had either dedicated menopause clinics or other clinics with a high volume of menopausal patients. Of all programs surveyed, only 29.3% reported that trainees had dedicated time assigned to a menopause clinic. A total of 83 of 99 PDs agreed or strongly agreed that their programs needed more menopause educational resources, and most (89.7%) stated they were likely or very likely to use self-paced menopause modules that include performance feedback if available. CONCLUSIONS: Data from the needs assessment questionnaire revealed that menopause education and resources vary across residency programs, with the majority lacking a dedicated menopause curriculum. Most PDs expressed a desire for more educational resources and standardized training materials, and preferred to access an online national menopause curriculum.

Oral Ibrexafungerp for Vulvovaginal Candidiasis Treatment: An Analysis of VANISH 303 and VANISH 306.

Background: Ibrexafungerp is a novel antifungal treatment for acute vulvovaginal candidiasis (VVC). Using pooled data from two phase three studies (VANISH 303 and 306) in the treatment of acute VVC, this analysis sought to determine the effectiveness of ibrexafungerp in various patient subgroups that may impact outcomes. Materials and Methods: Data from VANISH 303 (NCT03734991) and VANISH 306 (NCT03987620) evaluating ibrexafungerp 300 mg twice daily (BID) for 1 day versus placebo, were pooled and analyzed to determine clinical cure rate, clinical improvement, and mycological cure at the test-of-cure visit (day 11 ± 3) and symptom resolution at the follow-up visit (day 25 ± 4) in the overall population. Patient subgroups analyzed included race, body mass index (BMI), baseline vulvovaginal signs and symptoms (VSS) score, and Candida species. Results: At the test-of-cure visit, patients receiving ibrexafungerp, compared with those who received placebo, had significantly higher rates of clinical cure (56.9% [214/376 patients] vs. 35.7% [65/182 patients]), clinical improvement (68.4% [257/376 patients] vs. 45.1% [82/182 patients]), and mycological cure (54.0% [203/376 patients] vs. 24.2% [44/182 patients]; all p < 0.0001). At the follow-up visit, patients receiving ibrexafungerp had sustained responses with higher symptom resolution rates (66.8% [251/376 patients]) versus placebo (48.4% [88/182 patients]; p < 0.0001). Race, BMI, baseline VSS score (including VSS severity score 13-18), and Candida species infection did not adversely affect clinical cure rates. Safety analysis results were consistent with the individual studies. Conclusions: Ibrexafungerp provides a safe and well-tolerated first-in-class fungicidal, 1-day oral treatment for patients with acute VVC, the first new therapy in >20 years. Clinical Trial Registration Number: NCT03734991.

A core outcome set for genitourinary symptoms associated with menopause: the COMMA (Core Outcomes in Menopause) global initiative.

OBJECTIVE: Genitourinary symptoms, such as vaginal dryness and pain with sex, are commonly experienced by postmenopausal women. Comparing treatments for these genitourinary symptoms are restricted by the use of different outcome measures in clinical trials and the omission of outcomes, which may be relevant to women. The aim of this project was to develop a Core Outcome Set (COS) to be reported in clinical trials of treatments for genitourinary symptoms associated with menopause. METHODS: We performed a systematic review of randomized controlled trials of treatments for genitourinary symptoms associated with menopause and extracted their outcomes. This list was refined and entered into a two-round modified Delphi survey, which was open to clinicians, researchers, and postmenopausal women from November 2019 to March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." The final COS was determined following two international consensus meetings. RESULTS: A total of 26 unique outcomes were included in the Delphi process, which was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to the Delphi scores to categorize outcomes by importance, which informed the e consensus meetings, attended by 43 participants from 21 countries. The final COS includes eight outcomes: (1) pain with sex, (2) vulvovaginal dryness, (3) vulvovaginal discomfort or irritation, (4) discomfort or pain when urinating, (5) change in most bothersome symptom, (6) distress, bother or interference of genitourinary symptoms, (7) satisfaction with treatment, (8) side effects of treatment. CONCLUSION: These eight core outcomes reflect the joint priorities of postmenopausal women, clinicians, and researchers internationally. Standardized collection and reporting of these outcomes in clinical trials will facilitate the comparison of different treatments for genitourinary symptoms, advance clinical practice, and ultimately improve outcomes for symptomatic women.

Video Summary:http://links.lww.com/MENO/A765 .

A core outcome set for vasomotor symptoms associated with menopause: the COMMA (Core Outcomes in Menopause) global initiative.

OBJECTIVE: Vasomotor symptoms (VMS) (hot flashes and night sweats) affect most women over the menopause transition. Comparing the safety and effectiveness of treatments for vasomotor symptoms is limited by the use of inconsistent outcome measures, and uncertainty as to which outcomes are most important to symptomatic women. To address this, we have developed a Core Outcome Set (COS) for use in clinical trials of treatments for VMS. METHODS: We systematically reviewed the primary outcomes measured in randomized controlled trials of treatments for VMS. These were refined and entered into a two-round modified Delphi survey completed by clinicians, researchers, and postmenopausal women between November 2019 and March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." Two international consensus meetings were held to finalize the COS. RESULTS: Based on the systematic review, 13 separate outcomes were included in the Delphi process. This was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to categorize importance scores obtained during Round 2 of the Delphi survey. These informed discussions at the consensus meetings which were attended by 56 participants from 28 countries. The final COS includes six outcomes: 1) frequency of VMS, 2) severity of VMS, 3) distress, bother or interference caused by VMS, 4) impact on sleep, 5) satisfaction with treatment, and 6) side-effects of treatment. CONCLUSION: Implementation of this COS will: better enable research studies to accurately reflect the joint priorities of postmenopausal women, clinicians and researchers, standardize outcome reporting, and facilitate combining and comparing results from different studies, and ultimately improve outcomes for women with bothersome VMS.

Video Summary:http://links.lww.com/MENO/A763 .

Endometrial safety and bleeding profile of a 17ß-estradiol/progesterone oral softgel capsule (TX-001HR).

OBJECTIVE: The aim of the study was to evaluate the effect of a single-capsule 17ß-estradiol/progesterone (E2/P4), TX-001HR, on endometrial safety, to report on amenorrhea and bleeding patterns of users, and to identify predictors of amenorrhea. METHODS: The REPLENISH trial (NCT01942668) evaluated use of TX-001HR in menopausal women (40-65 y) with vasomotor symptoms (VMS) and a uterus. Women were randomized to daily E2/P4 (mg/mg: 1/100, 0.5/100, 0.5/50, or 0.25/50), or placebo for 12 months. Incidence rate of endometrial hyperplasia was calculated from endometrial biopsies conducted at screening and study completion. Women reported bleeding and spotting in daily diaries. The number of bleeding and/or spotting days and the proportion of women with no bleeding or amenorrhea were compared between treatment and placebo using the Fisher exact test. Predictors of cumulative amenorrhea were assessed by univariate analyses. RESULTS: Women (n = 1,835) who took at least one study dose comprised the safety population; 1,255 had baseline and 12-month biopsies and comprised the endometrial safety population. Incidence of endometrial hyperplasia was ≤0.36% with any dose of TX-001HR after 1 year of use (one-sided upper 95% confidence interval ≤4%). Cumulative amenorrhea (no bleeding/spotting) rates increased over time and were relatively high from cycle 1 to 13 with TX-001HR (56%-73%; placebo 79%; P < 0.05 except with 0.25/50 dose). Few vaginal bleeding adverse events (1.0%-4.6% TX-001HR vs 0.7% placebo) were reported and discontinuations due to bleeding were low (0.4%-1.4% vs 0%). Cumulative amenorrhea was significantly more frequent in older women, those further from their last menstrual period, and those with lower baseline E2 concentrations (all; P < 0.01). CONCLUSIONS: All doses of TX-001HR provided endometrial protection and were associated with an improved bleeding profile over time; older age, further last menstrual period, or lower baseline E2 may predict amenorrhea with TX-001HR.

O-RADS US Risk Stratification and Management System: A Consensus Guideline from the ACR Ovarian-Adnexal Reporting and Data System Committee.

The Ovarian-Adnexal Reporting and Data System (O-RADS) US risk stratification and management system is designed to provide consistent interpretations, to decrease or eliminate ambiguity in US reports resulting in a higher probability of accuracy in assigning risk of malignancy to ovarian and other adnexal masses, and to provide a management recommendation for each risk category. It was developed by an international multidisciplinary committee sponsored by the American College of Radiology and applies the standardized reporting tool for US based on the 2018 published lexicon of the O-RADS US working group. For risk stratification, the O-RADS US system recommends six categories (O-RADS 0-5), incorporating the range of normal to high risk of malignancy. This unique system represents a collaboration between the pattern-based approach commonly used in North America and the widely used, European-based, algorithmic-style International Ovarian Tumor Analysis (IOTA) Assessment of Different Neoplasias in the Adnexa model system, a risk prediction model that has undergone successful prospective and external validation. The pattern approach relies on a subgroup of the most predictive descriptors in the lexicon based on a retrospective review of evidence prospectively obtained in the IOTA phase 1-3 prospective studies and other supporting studies that assist in differentiating management schemes in a variety of almost certainly benign lesions. With O-RADS US working group consensus, guidelines for management in the different risk categories are proposed. Both systems have been stratified to reach the same risk categories and management strategies regardless of which is initially used. At this time, O-RADS US is the only lexicon and classification system that encompasses all risk categories with their associated management schemes.

Abnormal Uterine Bleeding.

Abnormal uterine bleeding (AUB) is a common medical problem, with a direct influence on women's quality of life, utilization of health care resources, and costs. AUB in women older than 40 years and especially in postmenopausal women requires a prompt and efficient evaluation, mainly to exclude the presence of malignant or premalignant lesions of the endometrium. Cancer of the endometrium is the most common gynecologic malignancy, with an incidence in the United States of more than 60,000 cases and mortality estimated at 10,000 women annually. This article outlines the role of transvaginal ultrasonography in the evaluation of cases of AUB.

Ospemifene for the treatment of menopausal vaginal dryness, a symptom of the genitourinary syndrome of menopause.

Introduction: Vulvovaginal atrophy (VVA), a component of the genitourinary syndrome of menopause, is a progressive condition due to decline in estrogen leading to vaginal and vulvar epithelial changes. Accompanying symptoms of dryness, irritation, burning, dysuria, and/or dyspareunia have a negative impact on quality of life. Ospemifene is a selective estrogen receptor modulator (SERM) approved by the FDA for moderate to severe dyspareunia and vaginal dryness due to postmenopausal VVA. Areas covered: PubMed was searched from inception to March 2019 with keywords ospemifene and vulvar vaginal atrophy to review preclinical and clinical data describing the safety and efficacy of ospemifene for vaginal dryness and dyspareunia due to VVA. Covered topics include efficacy of ospemifene on vaginal cell populations, vaginal pH, and most bothersome VVA symptoms; imaging studies of vulvar and vaginal tissues; effects on sexual function; and safety of ospemifene on endometrium, cardiovascular system, and breast. Expert opinion: Ospemifene is significantly more effective than placebo in all efficacy analyses studied, working through estrogen receptors and possibly androgen receptors. Safety as assessed by adverse events was generally comparable to that with placebo and to other SERMs, and/or adverse events were not clinically meaningful. No cases of endometrial or breast cancer were reported.

Simple Adnexal Cysts: SRU Consensus Conference Update on Follow-up and Reporting.

This multidisciplinary consensus update aligns prior Society of Radiologists in Ultrasound (SRU) guidelines on simple adnexal cysts with recent large studies showing exceptionally low risk of cancer associated with simple adnexal cysts. Most small simple cysts do not require follow-up. For larger simple cysts or less well-characterized cysts, follow-up or second opinion US help to ensure that solid elements are not missed and are also useful for assessing growth of benign tumors. In postmenopausal women, reporting of simple cysts greater than 1 cm should be done to document their presence in the medical record, but such findings are common and follow-up is recommended only for simple cysts greater than 3-5 cm, with the higher 5-cm threshold reserved for simple cysts with excellent imaging characterization and documentation. For simple cysts in premenopausal women, these thresholds are 3 cm for reporting and greater than 5-7 cm for follow-up imaging. If a cyst is at least 10%-15% smaller at any time, then further follow-up is unnecessary. Stable simple cysts at initial follow-up may benefit from a follow-up at 2 years due to measurement variability that could mask growth. Simple cysts that grow are likely cystadenomas. If a previously suspected simple cyst demonstrates papillary projections or solid areas at follow-up, then the cyst should be described by using standardized terminology. These updated SRU consensus recommendations apply to asymptomatic patients and to those whose symptoms are not clearly attributable to the cyst. These recommendations can reassure physicians and patients regarding the benign nature of simple adnexal cysts after a diagnostic-quality US examination that allows for confident diagnosis of a simple cyst. Patients will benefit from less costly follow-up, less anxiety related to these simple cysts, and less surgery for benign lesions.

Efficacy and safety of ospemifene in postmenopausal women with moderate-to-severe vaginal dryness: a phase 3, randomized, double-blind, placebo-controlled, multicenter trial.

OBJECTIVE: To evaluate the safety and efficacy of ospemifene for the treatment of moderate to severe vaginal dryness in postmenopausal women with vulvovaginal atrophy (VVA). METHODS: This 12-week, multicenter, double-blind phase 3 study randomized postmenopausal women (aged 40-80 years) with VVA and moderate to severe vaginal dryness as their most bothersome symptom to daily oral ospemifene 60 mg or placebo. Coprimary efficacy endpoints included changes from baseline to week 12 in percentages of vaginal parabasal and superficial cells, vaginal pH, and vaginal dryness severity with ospemifene versus placebo; other secondary endpoints were evaluated (weeks 4, 8, and 12). Safety was assessed by treatment-emergent adverse events (TEAEs) and endometrial biopsies. RESULTS: Women (n = 631; ospemifene [n = 316], placebo [n = 315]) had a mean age of 59.8 years, a mean body mass index of 27.2 kg/m, and most were white. Ospemifene significantly improved (P < 0.0001) the percentages of parabasal and superficial cells, vaginal pH, and severity of vaginal dryness severity compared with placebo at week 12; significant between-group differences were noted by week 4. Secondary endpoints of dyspareunia (P < 0.001), maturation value (P < 0.0001), and the Female Sexual Function Index (P < 0.05) also significantly improved with ospemifene versus placebo at week 12. Significantly more women responded (31.5% vs 6.0%; P < 0.0001) or were satisfied (49.2% vs 33.8%; P = 0.0007) with ospemifene versus placebo at week 12. No unexpected TEAEs, treatment-related serious TEAEs, thrombotic events, or endometrial hyperplasia or carcinoma were observed. CONCLUSIONS: Ospemifene was effective and well tolerated for the treatment of moderate-to-severe vaginal dryness in postmenopausal women with VVA.

Increased Incidence of Endometrial Cancer Following the Women's Health Initiative: An Assessment of Risk Factors.

BACKGROUND: The Surveillance, Epidemiology, and End Result (SEER) database shows a variable increase in endometrial cancer incidence over time. The objective of this review was to examine published endometrial cancer rates and potential etiologies. METHODS: Endometrial cancer incidence was obtained from the SEER Program database from 1975 through 2014, and a test for trend in incidence was calculated. Changes in risk factors thought to be associated with endometrial cancer, including age, obesity, diabetes, diet and exercise, reproductive factors, and medications (hormone therapy [HT] including Food and Drug Administration [FDA]-approved and non-FDA-approved [compounded] estrogens and progestogens, tamoxifen, and hormonal contraceptives) were found through PubMed searches. Temporal trends of risk factors were compared with endometrial cancer trends from SEER. RESULTS: Although endometrial cancer rates were constant from 1992 to 2002 (women 50-74 years of age), they increased 2.5% annually with a 10% increase from 2006 to 2012 (trend test 0.82). Use of approved prescription estrogen-progestogen combination products decreased after the publication of the Women's Health Initiative (WHI) data, whereas other risk factors either remained constant or decreased during the same time; however, compounded bioidentical HT (CBHT) use increased coincident with the endometrial cancer increase. CONCLUSION: Endometrial cancer rate increases after the first publication of WHI data in 2002 may be associated with the decreased use of approved estrogen-progestogen therapy, the increase in CBHT use, and the prevalence of obesity and diabetes; potential relationships require further evaluation.

Appropriate evaluation of postmenopausal bleeding.

: In clinical practice, although only 3% to 7% of women with postmenopausal bleeding (PMB) will ultimately be found to have cancer, it is the clinician's responsibility to ensure that endometrial cancer is not present. The diagnostic evaluation of PMB has evolved greatly. This Practice Pearl addresses the appropriate evaluation of women with PMB.

Ovarian-Adnexal Reporting Lexicon for Ultrasound: A White Paper of the ACR Ovarian-Adnexal Reporting and Data System Committee.

Ultrasound is the most commonly used imaging technique for the evaluation of ovarian and other adnexal lesions. The interpretation of sonographic findings is variable because of inconsistency in descriptor terminology used among reporting clinicians. The use of vague terms that are inconsistently applied can lead to significant differences in interpretation and subsequent management strategies. A committee was formed under the direction of the ACR initially to create a standardized lexicon for ovarian lesions with the goal of improving the quality and communication of imaging reports between ultrasound examiners and referring clinicians. The ultimate objective will be to apply the lexicon to a risk stratification classification for consistent follow-up and management in clinical practice. This white paper describes the consensus process in the creation of a standardized lexicon for ovarian and adnexal lesions and the resultant lexicon.

An evidence-based approach to assessing surgical versus clinical diagnosis of symptomatic endometriosis.

Challenges intrinsic to the accurate diagnosis of endometriosis contribute to an extended delay between the onset of symptoms and clinical confirmation. Intraoperative visualization, preferably with histologic verification, is considered by many professional organizations to be the gold standard by which endometriosis is diagnosed. Clinical diagnosis of symptomatic endometriosis via patient history, physical examination, and noninvasive tests, though more easily executed, is generally viewed as less accurate than surgical diagnosis. Technological advances and increased understanding of the pathophysiology of endometriosis warrant continuing reevaluation of the standard method for diagnosing symptomatic disease. A review of the published literature was therefore performed with the goal of comparing the accuracy of clinical diagnostic measures with that of surgical diagnosis. The current body of evidence suggests that clinical diagnosis of symptomatic endometriosis is more reliable than previously recognized and that surgical diagnosis has limitations that could be underappreciated. Regardless of the methodology used, women with suspected symptomatic endometriosis would be well served by a diagnostic paradigm that is reliable, conveys minimal risk of under- or over-diagnosis, lessens the time from symptom development to diagnosis, and guides the appropriate use of medical and surgical management strategies.