Faculty Bibliography

OBJECTIVE:The aim of the study was to evaluate the effect of a single-capsule 17β-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.

Research into non-hormonal, alternative therapies is necessary for women for whom menopausal hormone therapy is contraindicated or for women who do not wish to take hormones. This review focuses on one such non-hormonal option, namely, purified and specific cytoplasmic pollen extract, or PureCyTonin^®. This extract has been evaluated in several preclinical and clinical studies, where it demonstrated its value as a safe and non-estrogenic alternative for menopause. This review presents the beneficial effects of PureCyTonin^® in the treatment of menopausal symptoms (e.g. hot flushes) in healthy women, as well as in premenstrual syndrome. We discuss the mechanism of action of PureCyTonin^®, an SSRI-'like' therapy. The lack of estrogenic effect demonstrated in preclinical studies suggests that PureCyTonin^® may also be a suitable option for the management of menopausal symptoms in women with breast cancer.

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.

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.

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.

Study Objective: Compare how obstetrician/gynecologists (OBGYNs) in four English-speaking regions (Australia/New Zealand (ANZ), Canada (CAN), United Kingdom (UK), and United States of America (USA)) think of and use transvaginal ultrasound (TVS) in the diagnosis and management of endometriosis.
Design(s): An online survey.
Setting(s): Between May and November 2018, the online survey was distributed in ANZ, CAN, UK and USA. Patients or Participants: Independently-practicing OBGYNs belonging to the Royal Australian New Zealand College of Obstetricians and Gynaecologists, Society of Obstetricians and Gynaecologists of Canada, American College of Obstetricians and Gynecologists and British Society for Gynaecological Endoscopy.
Intervention(s): Questions on the diagnosis and management of endometriosis, with particular emphasis on the utility of ultrasound.
Measurements and Main Results: Questions were designed by the study team and piloted. The formal invitation was distributed via email through the respective societies with a reminder at two weeks. Responses were analyzed quantitatively using descriptive and inferential statistics. Missing data were excluded from the analysis. 1140 OBGYNs responded. Regional respondent number and response rate are as follows: ANZ 449(20.4%), CAN 156(10.4%), UK: 95(14.2%), US: 440(1.4%). 65 respondents were disqualified based on practice composition. Differences in the utilization of the deep endometriosis (DE) TVS were noted, with ANZ members seemingly adopting the technology more readily. Similarly, ANZ respondents had the highest rates of expectation/belief in the utility of TVS for endometriosis. A high rate of disbelief of TVS utility exists broadly. Lastly, US members ranked endometriomas as the most important feature of endometriosis predict on imaging preoperatively, whereas UK members ranked rectovaginal septum and ANZ/CAN members ranked bowel DE as most important, respectively.
Conclusion(s): Regional differences were noted in the awareness of utility and adoption of TVS for diagnosis of endometriosis. This study should serve as an important stepping stone in raising awareness and introducing educational campaigns to improve the utility and adoption of this essential preoperative and diagnostic tool.
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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.

SERMs are selective estrogen receptor modulators. Actually, clomiphene citrate was the first SERM, although for all practical purposes, tamoxifen, introduced in the late 1970's, is thought of as the first SERM. It results in increased survival and disease-free survival in women with breast cancer. It is the most widely prescribed anti-neoplastic drug worldwide. It has some untoward effects in the uterus and venous system. It is approved for breast cancer prevention as well. Raloxifene is approved for prevention and treatment of osteoporosis as well as breast cancer prevention. It is also thrombogenic in the venous system but does not cause pathologic changes like tamoxifen in the endometrium. TSEC (tissue specific estrogen complex)is a new concept of combining estrogen with a SERM instead of progestin for endometrial protection. Currently, the combination of conjugated estrogen and bazedoxifene is approved to treat vasomotor symptoms and prevent osteoporosis. Attempts to combine other estrogens with other SERMs have not been successful and such trials were halted because of an increase in endometrial hyperplasia.