Faculty Bibliography

OBJECTIVE: The aim of this study was to report the gynecologic safety findings from the Generations trial, a phase 3 study of the selective estrogen receptor modulator (SERM), arzoxifene. METHODS: A predefined objective of the trial was to evaluate the effects of arzoxifene on the genital tract. Gynecologic examinations were performed yearly, and further gynecologic assessment, including endometrial biopsy, was performed in a predefined subset of women and in those who developed vaginal bleeding. RESULTS: Overall, 9,354 women were randomized (4,678 to placebo, 4,676 to arzoxifene 20 mg/d). There were 13 adjudicated cases of endometrial cancer (placebo, 4 cases; arzoxifene, 9 cases: P = 0.165) and 6 cases of endometrial hyperplasia (placebo, 2 cases; arzoxifene, 4 cases). Endometrial thickness, assessed at 24- and 36-month transvaginal ultrasounds in a subset of women, increased slightly in women assigned to arzoxifene compared with baseline and women in placebo. At the last measurement, 3 (1.7%) women assigned to placebo and 21 (10.2%) assigned to arzoxifene had an endometrial thickness greater than 5 mm (P < 0.001 for difference between treatment groups). Endometrial polyps were more common in women treated with arzoxifene (n = 37) than in women treated with placebo (n = 18; P < 0.05). Vulvular and vaginal inflammation, including mycotic infections, and vaginal discharge were reported more frequently in women treated with arzoxifene than in women treated with placebo, as were urinary tract infections. CONCLUSIONS: Gynecologic events were generally more common in women treated with arzoxifene than in women treated with placebo. The gynecologic effects of arzoxifene seem to differ from those of raloxifene, although both SERMs have a benzothiophene structure. Although all SERMs influence cells through the estrogen receptor, they need to be evaluated independently in terms of their effects on various tissues, including the genital tract.

Objective: Currently, only estrogen-based preparations have received regulatory approval for prescription treatment of vulvovaginal atrophy (VVA) in postmenopausal women; therefore, exploring alternative treatments for WA is imperative. Ospemifene, a novel, selective estrogen receptor modulator (SERM), is unique compared with other SERMs due to its estrogenic activity in the vaginal epithelium and is under investigation in postmenopausal women with VVA symptoms. This study assessed the efficacy, safety, and tolerability of ospemifene 60 mg/d in the treatment of WA symptoms in postmenopausal women. Design: This 12-wk, randomized, double-blind, placebo-controlled, parallel-group study included 919 subjects. Two study populations were analyzed: intent-to-treat (ITT), the primary analysis, and per protocol (PP). Women (4080 years of age) were assigned to one of 2 VVA symptom strata (vaginal dryness or dyspareunia) based on their self-reported most bothersome WA symptom (MBS);and within each stratum were randomized 1:1 to receive either ospemifene 60 mg/d or placebo. Data from each stratum were independently analyzed. All subjects were provided with a nonhormonal vaginal lubricant to be used as needed (PRN). For each stratum, co-primary efficacy endpoints were measured for change from baseline to Wk 12 (LOCF) in: vaginal pH, % superficial cells and % parabasal cells in the maturation index, and the severity of the MBS. This abstract reports the dyspareunia stratum results. Results: At Wk 12 ospemifene demonstrated significant efficacy vs placebo for each co-primary endpoint. Changes in the ITT population for vaginal pH (LS mean),% of superficial cells (median), and % of parabasal cells (LS mean) all were p<0.0001 (Table 1); a significant effect was observed as early as 4 wks. Significant mean improvement was also observed for the MBS, dyspareunia (p=0.0001) at Wk 12. A higher percentage of subjects treated with ospemifene reported no, or mild dyspareunia and self-reported symptom severity that improved by 2-3 points on a 4-point Likert scale in 52.8% of ospemifene vs 38.8% of placebo subjects. The PP analysis also demonstrated statistically significant findings for each co-primary endpoint, confirming ll'i analysis. The % of subjects with at least 1 adverse event (in the ITT population) at Wk 12 for both strata combined is summarized in Table 2. Discontinuation rates were similar in the ospemifene and placebo groups, 10.2% vs 11.6%, respectively. Endometrial histology assessments showed no cases of hyperplasia and 2 (1.0%) cases of active proliferation in the ospemifene group vs 0% in the placebo group. Vaginal bleeding was reported in 2 (0.4%) and 4 (0.9%) subjects in the ospemifene and placebo groups, respectively. One subject in the ospemifene group experienced a deep vein thrombosis following an 8-hour car ride and was discontinued from the study. Conclusion: In postmenopausal women with self-reported MBS of dyspareunia, this unique study demonstrated that, despite the PRN use of lubricants, treatment with ospemifene 60 mg/d demonstrated clinically and statistically significant efficacy and was well tolerated. (Table Presented)

The ascertainment of diagnostic medical information through most of the 20th Century relied on techniques like inspection, palpation, and auscultation as noninvasive ways to obtain information about internal anatomy, both normal and abnormal, as well as physiology which when not normal we call "pathology". Sensitivity of imaging modalities has become so refined that we are seeing structures either never before appreciated or sometimes appreciated but not with such precision. This lecture will deal with my observations of this issue in gynecology using transvaginal ultrasound (TV U/S), although the problems associated with increased sensitivity of imaging exist in many other clinical fields as well. My thesis is that as we see more and more detail the response to what we see has often been based on old and thus preconceived notions, and not on newer well-organized and well-designed studies to determine the prevalence of particular findings and their clinical significance. Information obtained with increasingly refined technology cannot simply be handled according to old established principles. Newer studies must be made before clinical recommendations can be made. We must be careful not to over interpret such findings that may be much more common and less ominous that previously believed. The vaginal probe has revolutionized gynecology. Higher frequency probes in close proximity to the structure being studied have created a degree of image magnification that is as if we are doing ultrasound through a low power microscope (sonomicroscopy). We are seeing things with ultrasound that you cannot see with the naked eye. Furthermore, the ease of performing TV U/S, and its increasingly routine use for surveillance, has resulted, in my opinion, in an explosion of incidental findings that are much more common and more innocuous than previously realized. There are many examples in gynecology but I will concentrate on two that are very common and relevant to menopausal patients. These are 1) Simple ovarian cystic structures and 2) Incidental endometrial "thickening" in non bleeding postmenopausal women. Forty years ago the dictum that a palpable postmenopausal ovary was abnormal was put forth by Dr. Hugh Barber. When ultrasound (then transabdominal ultrasound) began to see postmenopausal cystic structures these were promptly removed as potentially malignant. 25 years ago the first small observational study began to suggest that unilocular unilateral cysts were invariably benign and could be managed expectantly. Abundant data from prospective screening studies have confirmed that observation. They have also shown the incidence of unilocular cystic adnexal structures in postmenopausal women can be as high as 18%. The field has "matured" to where almost all clinicians will now counsel such patients for conservative management. Twenty years ago the first reports of a thin distinct endometrial echo in postmenopausal patients with bleeding surfaced. Abundant prospective data from multicentered trials showed that the incidence of malignancy in postmenopausal patients with bleeding when the endometrial echo measures < 4mm on transvaginal ultrasound is 1/917. In 2009 ACOG stated "when transvaginal ultrasound is performed for patients with postmenopausal bleeding and an endometrial thickness <4mm is found endometrial sampling is not required". Unfortunately most clinicians who understood that a thin distinct endometrial echo in such patients excludes malignancy, have still inappropriately assumed that a thick echo in non-bleeding patients is abnormal and requires intervention. The prevalence of non thin endometrial echo on TV U/S in asymptomatic postmenopausal women is 10-17%. Furthermorel3% of asymptomatic postmenopausal women will have an endometrial polyp on TV U/S. The risk of malignancy is such imaged structures, absent bleeding, is less than 1 in 250 yet the complication rate from operative hysteroscopy in this elderly group is as high as 3.6%. The increasing sensitivity of the vaginal probe can and should be a wonderful tool for the gynecologist. However studies on the prevalence and significance of the things one can see on such imaging must be carried out if it is to be incorporated appropriately. Remember the credo -"above all else do no harm".

Objective: Ospemifene, a novel, selective estrogen receptor modulator (SERM) that exerts estrogenic, pharmacologic activity in the vaginal epithelium, is presently being studied for treatment of symptoms of vulvovaginal atrophy (WA) in postmenopausal women. This study assessed the efficacy, safety and tolerability of ospemifene 60 mg/d in the treatment of WA symptoms. Design: A 12-wk, 1:1 randomized, double-blind, placebo-controlled, parallel-group study enrolling 919 postmenopausal women 40 to 80 years of age with WA in two strata based on their self-reported most bothersome symptom (MBS) of vaginal dryness or vaginal pain (dyspareunia). Two study populations were analyzed: the intent-to-treat (TTT) (primary analysis) and per protocol (PP). Subjects in each stratum were randomized to receive 60 mg/d ospemifene or placebo and were provided with a nonhormonal vaginal lubricant to use as needed (PRN). For each stratum, changes from baseline to Wk 12 (LOCF) for the four co-primary endpoints were assessed: vaginal pH, percentages of superficial cells and parabasal cells in the maturation index and the severity of the MBS. This abstract reports the Dryness Stratum results. Results: In the TTT analysis, at Wk 12 ospemifene demonstrated significant efficacy vs placebo for 3 of 4 co-primary endpoints from baseline. Significant mean changes from baseline to Wk 12 for vaginal pH and percentages of superficial (LS mean) and parabasal cells (Median) were evident (Table 1). Significant improvement was observed as early as 4 wks. Improved mean change was observed for the MBS vaginal dryness at Wk 12, which approached statistical significance (P=0.0803). A higher % of subjects treated with ospemifene reported no vaginal dryness, and the subjects' self-reported symptom severity, which was assessed on a 4-point scale improved by 2 to 3 points in 46.3% ospemifene vs 34.4% placebo subjects. The PP analysis showed statistically significant improvement for all 4 co-primary endpoints (pH, % superficial and % parabasal cells, all P<0.0001 and vaginal dryness, P=0.0143) and similar improvements in dryness severity. The main difference between the ITT and the PP populations was in study drug compliance, which was higher in the PP population. The numbers of subjects with >1 adverse event (AE) at Wk 12 in both strata combined is summarized in Table 2. Discontinuation rates were similar in the ospemifene (10.2%) and placebo (11.6%) groups. Endometrial histology assessments showed no cases of hyperplasia and 2 (1.0%) cases of active proliferation in the ospemifene group vs 0% in the placebo group. Vaginal bleeding was reported in 2 (0.4%) and 4 (0.9%) subjects in the ospemifene and placebo groups, respectively; 1 subject on ospemifene experienced deep vein thrombosis was discontinued from the study. There were no cases of myocardial infarction, breast cancer or death. Conclusion: In postmenopausal women with the self-reported MBS of vaginal dryness, these data demonstrate that treatment with ospemifene 60 mg/d provides clinically and statistically significant efficacy and was well tolerated. With greater improvement in symptom severity scale changes and in markers of vaginal health, this novel SERM may prove to be the first non-estrogen to effectively treat the symptoms of WA. (Table Presented)

Introduction. Currently, only estrogen-based prescription preparations have received regulatory- authorization for the prescription treatment of vulvar and vaginal atrophy (VVA) in postmenopausal women. Therefore, clinical development of tissue-selective therapies to treat VVA which lack the undesired systemic effects of estrogen is warranted. Ospemifene, a selective estrogen receptor modulator (SERM), is differentiated from other SERMs by its estrogenic action in the vaginal epithelium, not on the endometrium, and is under investigation for use in postmenopausal women with VVA symptoms. This study evaluated the safety, efficacy, and estrogenic effects on the endometrium of ospemifene for up to 1 year; this abstract reports data for overall safety. Methods. A 52-wk, 6:1 randomized, double-blind, placebo-controlled, parallel-group study was conducted comparing 60 mg/d of oral ospemifene (n=363) with placebo (n=63) in postmenopausal women with VVA and an intact uterus. Clinical safety variables were assessed at screening, randomization and wks 12, 26, 39, 52 and 56. Results. A total of 22 (5.2%) subjects experienced >=1 SAEs. A numerically higher proportion of serious AEs (SAEs) were reported in the placebo group (6.5%) vs the ospemifene group (4.9%). In the ospemifene group, 1 (0.3%) subject had deep vein thrombosis, which resolved. No cases of pulmonary embolus, retinal vein thrombosis, or myocardial infarction were reported, and no subjects developed breast or endometrial cancer. Similar proportions of subjects (placebo, 75.8%; ospemifene, 84.6%) reported >1 treatment-emergent adverse event (AE); most were considered mild or moderate. The most commonly reported AE in the ospemifene group was hot flush (6.5% and 12.6%) for placebo (mean age 62.9 years) and ospemifene (mean age 61.7 years), respectively. The discontinuation rate for subjects in the ospemifene group who experienced hot flushes was approximately 2%.. Conclusion. Ospemifene 60 mg/d was found to be safe and well tolerated, in addition to efficacious, when used for the treatment of VVA in postmenopausal women with an intact uterus for up to 1 year

The sensitivity of transvaginal ultrasound has improved to the point where it is like doing ultrasound through a low powered microscope. Structures that could not be visualized with the naked eye can be seen. Simultaneously utilization of transvaginal ultrasound in all sorts of clinical applications has increased dramatically. There is also an increase in the use of other imaging modalities (MRI, CT), which often then result in recommending transvaginal ultrasound for corroboration. Thus incidental findings in postmenopausal women are often encountered. These include endometrial thickening without any history of bleeding, simple smooth walled ovarian cysts, and endometrial fluid. Information obtained with increasingly refined technology cannot simply be handled according to old concepts. New studies must be performed and the background incidence of such findings needs to be established. Available data would indicate that 10-17% of postmenopausal women have a simple cyst and 10-17% of women may also have increased endometrial thickening without any history of bleeding. The incidence of malignancy associated with such findings approaches zero but the cost, psychological burden and surgical morbidity is not insignificant. This presentation will discuss the available data on incidence and significance of incidental findings in postmenopausal women using transvaginal ultrasound