Faculty Bibliography

From the perspective of endometrial safety, there has been great controversy about what special management, if any, tamoxifen-treated patients should undergo. Periodic blind endometrial sampling or transvaginal ultrasound has been advocated by some. Because of the problems associated with either of these techniques alone, we recommended an approach that used transvaginal ultrasound and then proceeded to sonohysterography when the endometrial echo on transvaginal ultrasound was not reliably thin and distinct. The American College of Obstetricians and Gynecologists (ACOG), in its committee opinion, stated that patients receiving tamoxifen therapy should only have an annual pelvic exam with pap smear if they remain asymptomatic. Newer data suggest, however, that there are high- and low-risk groups that can be identified by pretreatment screening. Before tamoxifen therapy, 17% of patients have polyps. These patients have 17 times the incidence of atypical hyperplasia than those whose uterus was negative before tamoxifen therapy. Such findings call into question the validity of the only study of raloxifene where uterine safety was the primary endpoint. In that study, any woman with baseline endometrial findings other than pristinely negative (i.e., low risk) was excluded. However, other raloxifene studies without pretreatment screening show relative risk (RR) = 0.8 (95% CI = 0.2, 2.7) for endometrial carcinoma. This compares with the women over 50 years of age in the Breast Cancer Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-1) with tamoxifen when the RR = 4.01 (95% CI= 1.70, 10.90). The existence of potentially high- and low-risk groups should be taken into account in any future clinical trials looking at the endometrial safety of selective estrogen receptor modulators (SERMs)

OBJECTIVE:The aim of this study was to determine the incidence of ovarian cancer in postmenopausal women treated with raloxifene compared with placebo. METHODS:This analysis comprises integrated data from seven randomized, placebo-controlled trials of raloxifene (N = 9837). Ovarian cancer cases were identified from the safety database and reviewed by a gynecologic adjudication review board. RESULTS:Sixteen cases of ovarian cancer were reported: 8 women (79.4/100,000 patient-years) on placebo and 8 (37.4/100,000 patient-years) on pooled raloxifene doses. The relative risk of ovarian cancer associated with raloxifene therapy was 0.50 (95% confidence interval, 0.19-1.35). CONCLUSION/CONCLUSIONS:Raloxifene use was not associated with an increased risk for ovarian cancer.

OBJECTIVE: Endometrial polyps are relatively common in all groups of women. More polyps are being diagnosed with the widespread use of transvaginal ultrasound scanning and sonohysterography. The reported incidence of malignancy is low. The potential benefit of a noninvasive technique to distinguish benign from malignant polyps is obvious. This study was undertaken to evaluate endometrial polyps by color flow Doppler ultrasound scanning and histopathologic examination. STUDY DESIGN: This was an observational study of patients with an endometrial polyp on sonohysterography who underwent interrogation of their polyp with color Doppler ultrasound scanning and subsequently polypectomy. Polyp volume, resistive index, pulsatility index, indication for scan (bleeding vs incidental), and patient age were correlated with histopathologic type of the polyp (nonfunctional, proliferative, secretory, hyperplastic, or malignant). RESULTS: Of 61 patients studied, 42 patients (68.9%) were scanned for abnormal bleeding, and 19 patients (31.1%) had their polyps discovered incidentally. There were no statistically significant differences between histologic categories and the resistive index, pulsatility index, or size of the polyp. The age of patients with nonfunctional polyps was significantly greater than any other group (P <.001). Ninety-four percent of the functional polyps were discovered because of abnormal bleeding; 38% of the nonfunctional polyps were discovered incidentally (P <.001). CONCLUSION: The data suggest that the objective assessment of blood flow impedance (resistive index, pulsatility index) in endometrial polyps and the size of these polyps cannot replace surgical removal and pathologic evaluation to predict histologic type. Patients with nonfunctional polyps were older and less likely to have vaginal bleeding

Tamoxifen, the first clinically available SERM, was developed in 1966 and approved by the FDA (United States Food and Drug Administration) in 1978. It is the most prescribed antineoplastic drug in the world, with approximately 10 million women-use-years of experience. Tamoxifen has proved efficacious in all settings of breast cancer. However, in the mid-to-late 1980s, a series of letters to the editor and case reports announced an association between tamoxifen therapy in women with breast cancer and the development of endometrial carcinoma. Subsequently, in 1998, the observation of a significant 49% reduction in invasive breast cancer relative to placebo in a cohort of women at increased risk for the disease resulted in the early stopping of the National Surgical Adjuvant Breast and Bowel Project's (NSABP) P-1: Breast Cancer Prevention Trial (BCPT). Importantly, this was the first time that information became available about the effects of tamoxifen in healthy women, that is, women who did not already have breast cancer. In this healthy population, the relative risk of developing endometrial carcinoma in the tamoxifen arm was 2.54, although when stratified by age, in women over 50, the risk grew to 4.01. Thus, the risk appears to be confined to women over 50 because, in contrast, in women under 50 there was no statistically significant increase in the risk of endometrial carcinoma

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

In the mid 1980s when tamoxifen was shown to be associated with endometrial neoplasia there was a renewed interest in another SERM compound, raloxifene. Experimental animal data suggested that raloxifene did not stimulate the endometrium as tamoxifen does while having similar anti-oestrogenic effects in breast tissue as tamoxifen. Clinical data has now shown that raloxifene does not stimulate the endometrium in postmenopausal women. It results in no hyperplasia, no increase in endometrium thickness or polyp formation and virtually no proliferation. Further studies are necessary to see if long-term raloxifene use will reduce the risk of endometrial cancer. In studies of raloxifene as treatment for osteoporosis, when viewed as a secondary endpoint there was a significant reduction in risk of new onset breast cancer. Further studies with breast cancer as a primary endpoint are ongoing (the STAR Trial)

Selective oestrogen receptor modulators (SERMs) are structurally diverse non-steroidal compounds that bind to oestrogen receptors and produce oestrogen agonist effects in some tissues and oestrogen antagonist effects in others. SERMs are being evaluated for a number of oestrogen-related diseases, including post-menopausal osteoporosis, hormone-dependent cancers, and cardiovascular disease. Several compounds that exhibit a SERM profile are currently available for clinical use, including clomiphene, tamoxifen, and toremifene (which are triphenylethylenes) and raloxifene (a benzothiophene). Clomiphene is used for the induction of ovulation in sub-fertile women attempting pregnancy. Tamoxifen and toremifene are both used to treat breast cancer. Tamoxifen may have beneficial effects on bone mineral density and serum lipids. The effects of toremifene on serum lipids are similar to that of tamoxifen. Both compounds have stimulatory effects on the endometrium. Raloxifene, indicated for the treatment and prevention of post-menopausal osteoporosis, has beneficial effects on bone mineral density and serum lipids, but does not increase the risk of endometrial hyperplasia or endometrial cancer. Recently, raloxifene was shown to reduce the incidence of vertebral fractures in otherwise healthy women with osteoporosis; in the same study, a reduced incidence of breast cancer was also observed. Similar to oestrogens, SERMs increase the incidence of venous thromboembolism. Several newer compounds that exhibit a SERM profile are also in clinical development, including other triphenylethylenes (droloxifene, idoxifene) and benzothiophenes (LY353381.HCl), benzopyrans (EM-800), and naphthalenes (CP-336,156)