Steven R. Goldstein

Lasofoxifene in Postmenopausal Women with Osteoporosis

BACKGROUND The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain. METHODS In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke. RESULTS Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group. CONCLUSIONS In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)

Evaluation of the woman with postmenopausal bleeding: Society of radiologists in ultrasound-sponsored consensus conference statement

A panel of 14 physicians practicing medicine in the United States with expertise in radiology, obstetrics and gynecology, gynecologic oncology, hysteroscopy, epidemiology, and pathology was convened by the Society of Radiologists in Ultrasound to discuss the role of sonography in women with postmenopausal bleeding. Broad objectives of this conference were (1) to advance understanding of the utility of different diagnostic techniques for evaluating the endometrium in women with postmenopausal bleeding; (2) to formulate useful and practical guidelines for evaluation of women with postmenopausal bleeding, specifically as it relates to the use of sonography; and (3) to offer suggestions for future research projects.

Management of asymptomatic ovarian and other adnexal cysts imaged at US: Society of Radiologists in Ultrasound Consensus Conference Statement.

The Society of Radiologists in Ultrasound convened a panel of specialists from gynecology, radiology, and pathology to arrive at a consensus regarding the management of ovarian and other adnexal cysts imaged sonographically in asymptomatic women. The panel met in Chicago, Ill, on October 27-28, 2009, and drafted this consensus statement. The recommendations in this statement are based on analysis of current literature and common practice strategies, and are thought to represent a reasonable approach to asymptomatic ovarian and other adnexal cysts imaged at ultrasonography.

Ultrasonography-based triage for perimenopausal patients with abnormal uterine bleeding

OBJECTIVE Abnormal perimenopausal bleeding is common and accounts for much medical and surgical intervention. This study was undertaken to evaluate an ultrasonography-based triage paradigm for perimenopausal patients with abnormal uterine bleeding. STUDY DESIGN Four hundred thirty-three perimenopausal patients with abnormal uterine bleeding (either metrorrhagia, menorrhagia, or both) were evaluated. In lieu of undergoing a sampling procedure they were brought back on days 4 to 6 of the subsequent bleeding cycle, when the endometrium was expected to be its thinnest. If a distinct endometrial echo < or = 5 mm (double layer) was imaged by endovaginal ultrasonography, dysfunctional uterine bleeding was diagnosed. If a thickened endometrial echo > 5 mm or no endometrial echo was reliably visualized, a saline infusion sonohysterography was performed. If saline infusion sonohysterography revealed a symmetric single-layer endometrial thickness < 3 mm, dysfunctional uterine bleeding was diagnosed. If focal lesions were noted (polyps, submucous myomas, focal thickening), the patient was scheduled for curettage with hysteroscopy. If the endometrium was globally thickened, nondirected office biopsy was performed. RESULTS A total of 341 patients (79%) had ultrasonographic evidence of no anatomic abnormality, and dysfunctional uterine bleeding requiring no further studies was diagnosed. Fifty-eight patients (13%) had focal polypold masses, all of which were removed hysteroscopically and confirmed pathologically. Twenty-two patients (5%) had submucous myomas; 10 patients (23%) had globally thickened endometrium on saline infusion sonohysterography, and then nondirected office sampling revealed hyperplasia in 5 and proliferation in 5. Two patients had technically inadequate saline infusion sonohysterography, and thus we proceeded to hysteroscopy with curettage. CONCLUSION Nondirected office biopsy alone without imaging would have potentially missed the diagnosis of focal lesions such as polyps, submucous myomas, and focal hyperplasia in up to 80 patients (18%). Our clinical algorithm for perimenopausal patients with abnormal uterine bleeding used unenhanced endovaginal ultrasonography followed by saline infusion sonohysterography for selected patients. This approach allowed for no endometrial sampling, nondirected sampling, or directed sampling depending on whether the ultrasonography-based triage revealed no anatomic abnormalities, globally thickened endometrial tissue, or focal abnormalities, respectively.

Unusual ultrasonographic appearance of the uterus in patients receiving tamoxifen

Abstract Tamoxifen is widely used as adjunctive therapy for patients with breast cancer and has been suggested as protection against the development of breast cancer in women at risk on the basis of heredity. It is a nonsteroidal estrogen antagonist, but like all antagonists it has some agonistic properties. Its administration should result in atrophic changes in the endometrium, but paradoxically some reports have found hyperplasia and even carcinomas developing prospectively in patients on tamoxifen therapy. Increasingly, endovaginal ultrasonography is being used for endometrial assessment in a wide variety of patients. This report is the first description of an unusual ultrasonographic finding in the uteri of some patients receiving tamoxifen. Initially believed to be endometrial in location, when viewed after fluid instillation (sonohysterogram) the heterogenous bizarre ultrasonographic appearance was actually found to represent small subendometrial sonolucencies in the proximal myometrium. Because none of these patients were clinically bleeding and all had inactive endometria on biopsy, it seems prudent not to overinterpret ultrasonography findings in patients receiving tamoxifen who have not had fluid-enhanced assessment. (A M J O BSTET G YNECOL 1994;170:447-51.)

A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium

Objective To determine the effects of a selective estrogen receptor modulator, raloxifene, on postmenopausal endometrium. Methods Healthy postmenopausal women (n = 415) were randomly assigned to one of the following four groups: 60 or 150 mg/day raloxifene hydrochloride, 0.625 mg/day conjugated equine estrogens, or placebo, and treated for 1 year. Endometrial biopsies were obtained in a blinded fashion at baseline and every 6 months after the ultrasound studies. Transvaginal ultrasound, with uterine size measurements, was done at baseline and at 3-month intervals. Saline-infusion sonohysterography was done at baseline and every 6 months. Results There were no statistically significant differences in baseline characteristics. Mean endometrial thickness, measured by transvaginal ultrasound, was unchanged from baseline to end point in the placebo and raloxifene groups, whereas in the estrogen group it was significantly thicker by 5.5 mm (P < .001). Mean uterine volume, calculated from transvaginal ultrasound measurements, was higher in the estrogen group only (22 cm3, P < .001). Of the 358 women with paired biopsies, endometrial hyperplasia was present in 2.1%, 0%, and 26.1% of the end-point biopsies in the placebo, raloxifene, and estrogen groups, respectively (P < .001). Proliferative endometrium was present in 2.1% of the end-point biopsies in the placebo group, 1.7% in the combined raloxifene groups, and 39.8% in the estrogen group (P < .001). Conclusion Raloxifene, at 60 or 150 mg/day for 1 year, did not stimulate the postmenopausal endometrium. End-point endometrial thickness, morphology, and uterine volume in the raloxifene groups were similar to those observed at baseline and in the placebo group.

Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome

OBJECTIVE To improve the interpretation of future studies in women who are initially diagnosed with a pregnancy of unknown location (PUL), we propose a consensus statement with definitions of population, target disease, and final outcome. DESIGN A review of literature and a series of collaborative international meetings were used to develop a consensus for definitions and final outcomes of women initially diagnosed with a PUL. RESULT(S) Global differences were noted in populations studied and in the definitions of outcomes. We propose to define initial ultrasound classification of findings into five categories: definite ectopic pregnancy (EP), probable EP, PUL, probable intrauterine pregnancy (IUP), and definite IUP. Patients with a PUL should be followed and final outcomes should be categorized as visualized EP, visualized IUP, spontaneously resolved PUL, and persisting PUL. Those with the transient condition of a persisting PUL should ultimately be classified as nonvisualized EP, treated persistent PUL, resolved persistent PUL, or histologic IUP. These specific categories can be used to characterize the natural history or location (intrauterine vs. extrauterine) of any early gestation where the initial location is unknown. CONCLUSION(S) Careful definition of populations and classification of outcomes should optimize objective interpretation of research, allow objective assessment of future reproductive prognosis, and hopefully lead to improved clinical care of women initially identified to have a PUL.

Use of ultrasonohysterography for triage of perimenopausal patients with unexplained uterine bleeding.

OBJECTIVE Concerns about pathologic anatomy in perimenopausal women with irregular vaginal bleeding have made invasive diagnostic procedures commonplace. This study evaluated the use of fluid instillation to enhance vaginal probe ultrasonographic examination of the endometrium in such patients. STUDY DESIGN This was a prospective study of 21 women between 40 and 52 years old with irregular vaginal bleeding. On day 4 to 6 of the menstrual cycle a 5.3F Soules intrauterine insemination catheter (Cook ObGyn, Spencer, Ind.) was inserted, and under direct ultrasonographic examination sterile saline solution was slowly infused. If present, any polyp or submucous myoma was noted and the endometrial thickness surrounding the fluid was measured. Invasive endometrial sampling was then carried out. RESULTS Of the 21 patients, 8 had obvious polypoid lesions and underwent triage for operative hysteroscopic removal. The pathology report confirmed benign polyps in all 8. Three patients had submucous myomas. Two had wire loop resectoscopic excision. The third, with a submucous myoma that extended to the serosal edge of the uterus, received expectant management. Nine patients had no obvious anatomic lesion and endometrial thickness of < or = 4 mm. Biopsy in all 9 of these patients revealed early proliferative endometrium. One patient had endometrial thickness of 8 mm; fractional curettage with hysterectomy revealed simple hyperplasia without atypia. CONCLUSIONS Endometrial fluid instillation to enhance vaginal ultrasonography in perimenopausal women can reliably distinguish between patients with minimal tissue whose bleeding may be of anovulatory origin and best treated with hormonal therapy and those patients with significant amounts and type of tissue in need of formal curettage. Furthermore, polyps may be distinguished from submucous myomas, which allows appropriate preoperative triage for operative hysteroscopy when indicated and eliminates the need for diagnostic hysteroscopy.

Terms, definitions and measurements to describe the sonographic features of the endometrium and intrauterine lesions: a consensus opinion from the International Endometrial Tumor Analysis (IETA) group

The IETA (International Endometrial Tumor Analysis group) statement is a consensus statement on terms, definitions and measurements that may be used to describe the sonographic features of the endometrium and uterine cavity on gray‐scale sonography, color flow imaging and sonohysterography. The relationship between the ultrasound features described and the presence or absence of pathology is not known. However, the IETA terms and definitions may form the basis for prospective studies to predict the risk of different endometrial pathologies based on their ultrasound appearance. Copyright

Raloxifene effect on frequency of surgery for pelvic floor relaxation.

OBJECTIVE To assess the effects of raloxifene therapy on the frequency of surgery for pelvic floor relaxation in postmenopausal women. METHODS This analysis used safety data through 3 years of treatment from three double‐masked, placebo‐controlled, randomized trials of raloxifene, which included 6926 postmenopausal women with uteri at entry. Studies 1 and 2 enrolled 969 nonosteoporotic, postmenopausal women who were assigned to 30, 60, or 150 mg per day raloxifene or placebo. Study 3 enrolled 5957 osteoporotic, postmenopausal women randomized to raloxifene 60 or 120 mg per day or placebo. Indications for any reported pelvic operations were identified, including procedures performed for pelvic organ prolapse or urinary incontinence. RESULTS A total of 34 (1.51%) women in the placebo group and 35 (0.75%) raloxifene‐treated women underwent surgical procedures for pelvic floor relaxation. The odds ratio (and 95% confidence interval) for pelvic floor repair in women assigned to raloxifene was 0.50 (0.31, 0.81). Thus, raloxifene therapy was associated with a significantly reduced risk for pelvic floor surgery (P < .005). CONCLUSION Raloxifene does not increase pelvic floor relaxation. An apparent protective effect on pelvic floor function warrants further investigation.