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.

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, the only prescription products with regulatory authorization for the treatment of moderate-to-severe vulvar and vaginal atrophy (VVA) are estrogen-based. Selective estrogen receptor modulators (SERMs) are a unique class of compounds, each with their own tissue-specific pharmacologic profile. Ospemifene is a new SERM, which exerts estrogenic action in the vaginal epithelium and is currently under investigation as a chronic treatment for VVA in postmenopausal women. Chronic therapy with any SERM warrants careful examination for any potential negative effects on the endometrium. This study was undertaken to evaluate for endometrial safety and for any estrogenic effects in the endometrium of once-daily ospemifene 60 mg for up to 1 year. Methods: A 52-wk, 6:1 randomized, double-blind, placebo-controlled, parallel-group study compared 60 mg/d of oral ospemifene (n=363) with placebo (n=63) in postmenopausal women with VVA and an intact uterus. Endometrial biopsies and transvaginal ultrasound (TVU) were performed at baseline and 52 wks. Results: No subjects developed endometrial cancer. In the ospemifene group, there were 3 (1.0%) cases of active proliferation and 1 (0.3%) case of endometrial hyperplasia (simple hyperplasia without atypia), which resolved. TVU and/or endometrial biopsy findings suspicious for endometrial polyps were reported as adverse events in similar proportions of subjects (placebo, 1.8%; ospemifene, 2.0%). None of the placebo subjects and 5 (1.4%) ospemifene 60 mg subjects reported vaginal bleeding or spotting. Of these 5 subjects, 1 had active proliferative endometrium and the remainder showed only post-menopausal atrophic endometrium on biopsies. Conclusion: Treatment of postmenopausal women experiencing VVA with ospemifene 60 mg/d for up to 1 year resulted in no significant estrogenic or clinically important adverse effects on the endometrial tissue compared with placebo; further supporting its potential usefulness for treating VVA