Faculty Bibliography

Selective estrogen receptor modulators are a new category of therapeutic agents that bind with high affinity to estrogen receptors and mimic the effect of estrogens in some tissues but act as estrogen antagonists in others. Tamoxifen, a triphenylethylene derivative, was the first clinically available selective estrogen receptor modulator. It is a potent antiestrogen in the breast, and its use in breast cancer patients has made it the most prescribed antineoplastic drug worldwide. It has estrogen-like activity on bone metabolism, and it also reduces cholesterol. However, its ability to produce proliferation, polyp formation, and even carcinomas in the endometrium is well known. A new selective estrogen receptor modulator, raloxifene, a benzothiopene derivative, has a clinical profile similar to that of tamoxifen. However, both preclinical and clinical studies reveal that, unlike tamoxifen, it is a pure antiestrogen in the uterus. It has recently been approved by the Food and Drug Administration for prevention of osteoporosis in postmenopausal women. This report reviews pertinent preclinical and currently available clinical studies about this new selective estrogen receptor modulator and discusses clinical applicability

To evaluate the effects of tamoxifen on leiomyomas and ovarian cysts in postmenopausal breast cancer patients, uterine and leiomyoma volumes were monitored sonographically in 17 postmenopausal women receiving postoperative tamoxifen for breast cancer; patients were examined twice with a mean of 1.18 +/- 0.17 years between examinations. The mean increase in leiomyoma volume was 1.26 +/- 0.73 cm3. The mean myoma volume was significantly larger at follow-up evaluation than at initial ultrasonography (5.75 +/- 1.09 cm3 versus 4.36 +/- 0.817 cm3, respectively; Wilcoxon signed rank test, P = 0.0218). Six women developed new leiomyomas. Of the 21 leiomyomas initially detected, 13 increased, six decreased, and two were unchanged in volume. The mean increase in uterine volume was 17.45 +/- 8.49 cm3. Three patients had simple ovarian cysts at initial ultrasonographic examination, two of which remained unchanged in size, and the third resolved. Two patients had newly developed simple ovarian cysts. The increase in uterine and leiomyoma volumes with the development of new leiomyomas and the persistence or development of ovarian cysts in some patients support the existence of agonistic tamoxifen effects. Serial measurements of uterine and leiomyoma volumes and surveillance for ovarian cysts is recommended for tamoxifen users

Tamoxifen has been shown to decrease the recurrence rate of breast cancer. Evidence that tamoxifen use may be associated with an increased risk of endometrial cancer has caused investigators to recommend routine invasive sampling. We have assessed a minimally invasive alternative for endometrial surveillance of tamoxifen-treated patients utilizing transvaginal ultrasound and saline infusion sonohysterography. Asymptomatic women (n = 44) with breast cancer on postoperative tamoxifen treatment were referred to our gynecological ultrasound unit. Initially, the endometrial echo was measured with unenhanced transvaginal ultrasound. If a distinct echo measured < or = 5 mm, no further procedure was performed. For thickened or inadequately visualized echoes, sonohysterography was performed. If a thin echo was noted on sonohysterography, no further procedure was performed. If focal changes were detected, hysteroscopy/dilatation and curettage (D&C) was performed. For generalized symmetrically thickened echoes, a blind biopsy was done. If sonohysterography was unsuccessful, hysteroscopy/D&C was performed. Eleven (25%) patients had thin unenhanced echoes of < or = 5 mm. Twenty-five (57%) patients had thickened endometrial echoes. Three (7%) had naturally occurring endometrial fluid outlining a polyp. An endometrial echo could not be visualized in five (11%) patients. Sonohysterography was successfully performed in 21 out of 30 (70%) patients with either thickened or non-visualized unenhanced echoes. Of these, two patients had thin endometria with coexisting myomas; seven had thin endometria with typical tamoxifen-induced subendometrial changes: and seven had focal polypoid thickening confirmed by hysteroscopy/D&C. Histology revealed carcinoma associated with two, proliferation in one and four polyps. Five patients had thickened unenhanced echoes with symmetrically thickened single-layer measurements on sonohysterography. Histology revealed that three were proliferative, one was inactive and one was hyperplastic. In the nine patients with unsuccessful sonohysterography, hysteroscopy/D&C revealed inactive endometria in six, and three polyps. Our paradigm of evaluating the endometrial response to tamoxifen is concluded to overcome the shortcomings of either unenhanced transvaginal ultrasound or blind biopsy alone while it kept the number of invasive sampling procedures to 55% (24 out of 44)

Saline infusion sonohysterography enhances endovaginal ultrasound examination of the uterine cavity in perimenopausal patients with abnormal uterine bleeding. It is easily and rapidly performed at minimal cost, is extremely well tolerated by patients, and is virtually devoid of complications. Its use can prevent invasive diagnostic procedures in some patients as well as optimize the preoperative triage process for those patients who will require therapeutic intervention

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

OBJECTIVE: Our purpose was to evaluate whether tamoxifen has estrogenic endometrial effects as defined by histologic study or alterations in steroid hormone receptor expression. STUDY DESIGN: Nineteen postmenopausal tamoxifen-treated breast cancer patients who also had endometrial sampling were identified from files in the Department of Obstetrics and Gynecology. To examine the subgroup of 15 polyps, age-matched, non-hormonally treated patients with polyps (n = 8) or atrophic endometria (n = 5) served as comparison groups. Proliferative (n = 3) and secretory (n = 5) endometria served as procedural controls. Immunohistochemical studies for steroid receptors (estrogen, progesterone) were performed. RESULTS: Glandular cell progesterone receptor was significantly increased and stromal cell estrogen receptor was significantly decreased in tamoxifen-treated versus atrophic endometria. Progesterone receptor staining was not significantly different in tamoxifen-treated versus control polyps, although staining was high in both groups. Stromal cell estrogen receptor staining was significantly reduced in tamoxifen-treated versus control polyps, although there were no histologic differences. Reduced stromal cell estrogen receptor and increased glandular cell progesterone receptor staining was found in all tamoxifen-treated endometria regardless of the diagnosis. CONCLUSION: The tamoxifen-associated changes in endometrial steroid receptors support an estrogenic effect that is independent of histologic diagnosis and duration of use. This may contribute to the pathogenesis of tamoxifen-associated polyps and carcinomas

It has been 25 years since the introduction of the palpable postmenopausal ovary syndrome. As diagnostic imaging techniques have improved, small findings imaged in the adnexa were often handled as if they had been palpated. Clinical management was not made on any scientific basis. New endovaginal probes afford a degree of image magnification that is as if we are doing ultrasonography through a low-power microscope ('sonomicroscopy'). More recent additions of CA 125 measurement, color flow Doppler, and advanced endoscopic surgical techniques have come into the picture. This report attempts to describe an approach to postmenopausal cystic adnexal masses that synthesizes available information and techniques. It is designed to prevent unnecessary surgery and to prevent undue anxiety but not to miss or, at the least, unduly delay the diagnosis of ovarian cancer when it is, in fact, present