Faculty Bibliography

Abnormal uterine bleeding is one of the most common presenting complaints encountered in a gynecologist's office or primary care setting. The availability of diagnostic tools, such as ultrasound, endometrial sampling, and diagnostic hysteroscopy has made it possible to promptly diagnose and treat an increasing number of menstrual disorders in an office setting. The incorporation of newer medical therapies: antifibrinolytic drugs, shorter hormone-free interval oral contraceptive pills, and levonorgestrel inserts along with office minimally invasive treatments operative hysteroscopy and endometrial ablations have proven to be powerful therapeutic arsenals to provide short-term relief of abnormal uterine bleeding, and potentially, avoiding or delaying the hysterectomy.

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.

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

Selective estrogen receptor modulators (SERMs) can act as estrogen agonists or estrogen antagonist depending on the target tissue. Tamoxifen was the first clinically available SERM and is highly effective for the prevention and treatment of breast cancer. Tamoxifen however has estrogen agonistic activity in the uterus and has been associated with an increased risk of endometrial hyperplasia and malignancy. Thus endometrial safety has been an important consideration in the development of all SERMs since then. Raloxifene, which is currently approved for prevention and treatment of postmenopausal osteoporosis, and for the prevention of breast cancer, does not result in endometrial hyperplasia or cancer. It does result in a slight increase in endometrial polyps. Lasofoxifene which has been shown to reduce fracture risk and decrease the incidence of breast cancer did not increase endometrial cancers or endometrial hyperplasia but did result in an increased incidence in vaginal bleeding, endometrial polyps ( all of which were inactive and atrophic) and endometrial "thickening" on transvaginal ultrasound. Ospemefene has been shown to have beneficial effects on the vaginal epithelium but does not cause endometrial cancer or hyperplasia. Bazodoxifene is effective in preventing and treating postmenopausal osteoporosis and does not cause endometrial thickening on ultrasound nor any hyperplasia or cancer. Arzoxifene was evaluated in a phase III trials for treating osteoporosis but its clinical development program was suspended. Further investigation of newer SERMs is warranted to more clearly define the endometrial safety of each of these agents

Postmenopausal bleeding is "endometrial cancer until proven otherwise". The incidence of cancer is reported as 1-14% although most studies are in the 3-7% range. The majority will actually bleed from inactive atrophic endometrium. In the early 1990's pilot studies began to suggest that a thin distinct endometrial echo <4-5 mm in postmenopausal patients with bleeding was associated with a lack of significant tissue and effectively excluded endometrial carcinoma. Since then several large prospective multinational trials in Europe have corroborated this. Taken together it appears that in patients with postmenopausal bleeding a thin distinct endometrial echo <4mm on transvaginal has a risk of endometrial cancer of 1 in 917. It is crucial that the examiner appreciate that not all uteri lend themselves to a meaningful ultrasound examination. Axial uterus, previous surgery, coexisting myomas, marked obesity, adenomyosis will result in a significant minority of such patients not yielding a reliable endometrial echo visualized with transvaginal sonography. In such cases saline infusion sonohysterography (SIS) may be helpful. SIS should be thought of as a subset of TV/US in cases in which the endometrium is not thin or not well visualized. Blind endometrial biopsy with suction piston biopsy instruments has been a standard approach in spite of a lack of appropriate validation especially in light of the fact that endometrial pathology is not always global. Transvaginal ultrasound can and should be the first approach to the postmenopausal patient with bleeding

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