Faculty Bibliography

Objective: Genitourinary syndrome of menopause (GMS), comprising vulvovaginal atrophy (VVA), impacts the health and quality of life of postmenopausal women. Genital symptoms of VVA include vaginal dryness as a most bothersome symptom (MBS) which over time leads to sexual dysfunction and emotional distress and remains a condition of unmet need. The objective of the study was to evaluate the safety and efficacy of ospemifene, an oral, selective estrogen receptor modulator and nonhormonal option, for the treatment of vaginal dryness as the MBS of postmenopausal women with VVA.
Design(s): This Phase 3, multicenter, randomized, double-blind, placebo-controlled study assessed the efficacy and safety of ospemifene in menopausal women with vaginal dryness as MBS of VVA. Eligible subjects were postmenopausal, age 40-80 with moderate to severe vaginal dryness as a self-reported MBS of VVA. Subjects were randomized dryness) and female sexual function index (FSFI).
Result(s): 631 subjects were enrolled into the study and included in the intention-to-treat (ITT) population (ospemifene=316; placebo=315). The differences between treatment groups in change from baseline to Week 12 for each of the co-primary efficacy endpoints were statistically significant (p < 0.0001). These differences between treatment groups for co-primary endpoints were change from baseline at Week 4, 8, and 12 were the response variable. Other endpoints evaluated included vaginal pain associated with sexual activity, percentage of responders (a composite of increase from baseline of >= 10 in maturation value, decrease of >= 0.5 in vaginal pH, and decrease of >= 1 in categorical score for severity of MBS of vaginal dryness) and female sexual function index (FSFI).
Result(s): 631 subjects were enrolled into the study and included in the intention-to-treat (ITT) population (ospemifene=316; placebo=315). The differences between treatment groups in change from baseline to Week 12 for each of the co-primary efficacy endpoints were statistically significant (p < 0.0001). These differences between treatment groups for co-primary endpoints were observed as early as Week 4 and continued through Weeks 8 and 12. The severity of vaginal pain associated with sexual activity, among the other VVA symptoms assessed, also showed a significantly greater reduction from baseline in the ospemifene group compared to placebo by week 12. The percentage of responders significantly increased in the ospemifene group compared to placebo at weeks 4 and continued through weeks 8 and 12 with a statistically significant increase in the FSFI score in the ospemifene group at week 12. In the safety population, overall treatment-emergent AEs (TEAE) were reported within Week 12 for 35.3% of subjects in the ospemifene group and 33.3% of subjects in the placebo group. There were no TEAEs of deep vein thrombosis or breast cancer, and no deaths. Consistent with previous trials, subjects with intact uteri showed a slight mean endometrial thickening with ospemifene treatment; a mean increase of 0.63 mm in the ospemifene group compared to a mean decrease of 0.23 mm in the placebo group. No cases of endometrial hyperplasia or carcinoma were observed.
Conclusion(s): The results of this double-blind, randomized, placebo-controlled Phase 3 trial support that ospemifene 60 mg daily may be efficacious and safe in the treatment of moderate or severe vaginal dryness as the MBS of VVA. Ospemifene demonstrated statistically significant superiority over placebo for all co-primary efficacy endpoints by Week 12. The effectiveness of ospemifene was evident at week 4 and maintained through the study at Weeks 8 and 12. Endometrial findings at 12 weeks showed slight increase in endometrial thickness and no cases of hyperplasia or carcinoma

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.

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 is easy to perform but 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-diagnosis or over-diagnosis, lessens the time from symptom development to diagnosis, and guides the appropriate use of medical and surgical management strategies.

Cancer of the endometrium (EM) is the most common type of gynecologic cancer in the United States. In 2017, an estimated 60,050 cases of this cancer will occur with an estimated 10,470 deaths. Vaginal bleeding is the presenting sign in more than 90% of postmenopausal (PM) patients with EM carcinoma. The majority of patients with postmenopausal vaginal bleeding (PMB) experience bleeding secondary to atrophic changes of the vagina or endometrium. However, depending on age and risk factors 1-14% will have EM cancer. Thus the clinical approach to PMB requires prompt and efficient evaluation to exclude or diagnose carcinoma. SHORTCOMINGS OF BLIND ENDOMETRIAL SAMPLING In 1991, after a single study by Stovall et al in women with known carcinoma reported 97.5% accuracy, blind EM sampling became the standard approach to patients with PMB. This was widely publicized, marketed and promoted and was rapidly accepted as, "standard of care." In a similar study, however, Guido et al performed blind EM sampling in 65 patients with known carcinoma in the operating room just prior to their hysterectomy. They missed 11/65 cancers (sensitivity only 83%) but, upon opening all those uteri, they reported that when the cancers occupied 50% or more of the EMsurface the biopsy was 100% accurate. Similar studies in women with known carcinomas yielded false negative rates of 16% and 32%, respectively. As a result, in 2012, ACOG, in its Practice Bulletin, acknowledged the primary role of EM sampling in such patients is to determine if carcinoma or premalignant lesions are present. The bulletin goes on to state that, "EM biopsy has high overall accuracy in diagnosing EM cancer when an adequate specimen is obtained and when the EM process is global. If the cancer occupies less than 50% of the surface area of EM cavity the cancer can be missed by blind individual biopsy. Therefore, these tests are only an endpoint when they reveal cancer or a typical complex hyperplasia." This has tremendous ramifications for clinical practice. Certainly, healthcare providers, especially in low resource areas, can begin the evaluation with a blind biopsy but if the results do not indicate cancer or atypical hyperplasia the evaluation is not complete, especially if bleeding persists. Thus, the concept of distinguishing global from focal pathologies is becoming increasingly understood and important. Transvaginal ultrasonography (TV U/S) has been explored as an alternative technique to indirectly visualize the EM. The earliest reports comparing TV U/S measurement of EM thickness in women with PMB with EM sampling consistently found that an EM thickness of less than or equal to 4-5mm in these patients reliably excluded EM cancer. Since that time a number of confirmatory multicenter trials have been completed. Because TV U/S in patients with PMB has an extremely high negative predictive value, it is a reasonable first approach to such patients. It is not possible to complete a meaningful TV U/S examination with a reliable measurement of EM thickness in all patients. An axial uterus, obesity, coexisting myomas, adenomyosis, or previous uterine surgery can contribute to difficulty in obtaining reliable TV U/S assessment of EM thickness and texture. Failure to adequately identify a thin, distinct EM thickness in a PM woman with bleeding should trigger some alternative method of evaluation, like saline infusion sonohysterography (SIS) or hysteroscopy, preferably in an office setting. Since there has been widespread use of TV U/S to exclude pathology in PM women with bleeding, some clinicians have inappropriately extrapolated this information to assume that a thick echo discovered incidentally is abnormal and requires investigation. Data indicates that 13% of asymptomatic PM women will have an endometrial polyp. In a large multicenter trial in which 1152 polyps in non-bleeding PM women were removed only 1 contained a cancer, yet the serious complication rate from such removals is reported as 3.6%Thus, an EM measurement greater than 4mm incidentally discovered in a PM patient without bleeding need not routinely trigger evaluation, although, an individualized assessment based on patient characteristics and risk factors is appropriate

Objective: Uterine bleeding can be associated with endometrial pathology. Case reports1-3 and a North American Menopause Society survey (n=1064)4 suggest a potential increase in uterine bleeding and endometrial cancer with compounded bio-identical hormone therapy (CBHT). TX- 001HR (TherapeuticsMD, Boca Raton, FL) is an investigational, single, oral softgel capsule of combined 17b-estradiol/progesterone (E2/ P4; sometimes referred to as bio-identical hormones) currently being developed to treat vasomotor symptoms (VMS), while protecting the endometrium, in menopausal women. The objective of this analysis was to evaluate uterine bleeding in the REPLENISH trial with TX-001HR vs placebo. Design: Menopausal women (40-65 years) with VMS and an intact uterus were enrolled in REPLENISH (NCT01942668), a phase 3, randomized, doubleblind, placebo-controlled, multicenter trial. Women with moderate-tosevere hot flushes (-7/day or -50/week) were in the VMS substudy and randomized 1:1:1:1:1 to daily E2/P4 of 1.0 mg/100 mg, 0.5 mg/100 mg, 0.5mg/50 mg, 0.25mg/50 mg or placebo; all other women were randomized 1:1:1:1 to E2/P4 only for assessing endometrial safety. All women completed daily bleeding (requiring sanitary protection) and spotting (not requiring sanitary protection) diaries up to month 12. Bleeding profiles, including cumulative amenorrhea (no bleeding or spotting) were assessed over thirteen 28-day cycles in women who took -1 treatment capsule. Results: Women (n=1835) were randomized to daily E2/P4 of 1.0 mg/ 100 mg (n=415), 0.5 mg/100 mg (n=424), 0.5mg/50 mg (n=421), 0.25mg/50mg (n=424) or placebo (n=151). Cumulative amenorrhea from cycle 1 to 13 was high with TX-001HR (56-73%), but lower than with placebo (81%; Fig 1A), and increased over time. Women with no bleeding was high (74-90%) with TX-001HR (Fig 1B). Few vaginal bleeding adverse events (1.0-4.6% TX-001HR vs 0.7% placebo) were reported and discontinuation due to bleeding was low (<1.5%). Conclusion: TX-001HR was associated with high amenorrhea rates and adequate endometrial protection in menopausal women with VMS and an intact uterus. Uterine bleeding and spotting improved over time; the potential for bleeding and abnormal pathology may be largely avoided with adequate doses of progesterone as studied with TX-001HR. TX-001HR, if approved, may provide the first oral combination of estradiol/progesterone for the treatment of VMS in menopausal womenwith an intact uterus, including themillions using unapproved and inadequately studied CBHT

Abnormal uterine bleeding is one of the commonest presenting complaints encountered in a gynecologist's office or primary-care setting. The wider availability of diagnostic tools has allowed prompt diagnosis and treatment of an increasing number of menstrual disorders in an office setting. This White Paper reviews the advantages and disadvantages of transvaginal ultrasound, blind endometrial sampling and diagnostic hysteroscopy. Once a proper diagnosis has been established, appropriate therapy may be embarked upon. Fortunately, only a minority of such patients will have premalignant or malignant disease. When bleeding is sufficient to cause severe anemia or even hypovolemia, prompt intervention is called for. In most of the cases, however, the abnormal uterine bleeding will be disquieting to the patient and significantly affect her 'quality of life'. Sometimes, reassurance and expectant management will be sufficient in such patients. Overall, however, in cases of benign disease, some intervention will be required. The use of oral contraceptive pills especially those with a short hormone-free interval, the insertion of the levonorgestrel intrauterine system, the incorporation of newer medical therapies including antifibrinolytic drugs and selective progesterone receptor modulators and minimally invasive treatments have made outpatient therapy increasingly effective. For others, operative hysteroscopy and endometrial ablation are proven therapeutic tools to provide both long- and short-term relief of abnormal uterine bleeding, thus avoiding, or deferring, hysterectomy.

The First International Consensus Conference on Adnexal Masses was convened to thoroughly examine the state of the science and to formulate recommendations for clinical assessment and management. The panel included representatives of societies in the fields of gynecology, gynecologic oncology, radiology, and pathology and clinicians from Europe, Canada, and the United States. In the United States, there are approximately 9.1 surgeries per malignancy compared to the European International Ovarian Tumor Analysis center trials, with only 2.3 (oncology centers) and 5.9 (other centers) reported surgeries per malignancy, suggesting that there is room to improve our preoperative assessments. The American College of Obstetricians and Gynecologists Practice Bulletin on "Management of Adnexal Masses," reaffirmed in 2015 (Obstet Gynecol 2007; 110:201-214), still states, "With the exception of simple cysts on a transvaginal ultrasound finding, most pelvic masses in postmenopausal women will require surgical intervention." The panel concluded that patients would benefit not only from a more conservative approach to many benign adnexal masses but also from optimization of physician referral patterns to a gynecologic oncologist in cases of suspected ovarian malignancies. A number of next-step options were offered to aid in management of cases with sonographically indeterminate adnexal masses. This process would provide an opportunity to improve risk stratification for indeterminate masses via the provision of alternatives, including but not limited to evidence-based risk-assessment algorithms and referral to an "expert sonologist" or to a gynecologic oncologist. The panel believed that these efforts to improve clinical management and preoperative triage patterns would ultimately improve patient care.