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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; the Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts; and the Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida.
Address reprint requests to: Steven R. Goldstein, MD, Department of Obstetrics and Gynecology, NYU Medical Center, 530 First Avenue, New York, NY 10016
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Abstract |
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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.
Raloxifene is a benzothiophene-derived selective estrogen receptor modulator that acts as an estrogen agonist on bone and serum lipid metabolism and as an estrogen antagonist in the breast and uterus.1 Raloxifene therapy maintains bone mineral density (BMD) in healthy postmenopausal women.2 In the Multiple Outcomes of Raloxifene Evaluation trial, the risk of invasive breast cancer was decreased by 76% in postmenopausal women with osteoporosis who were treated with raloxifene for a median of 40 months.3 In the same study, raloxifene treatment was associated with a decreased incidence of new vertebral fractures. Raloxifene therapy also decreased serum cholesterol levels4 and did not increase endometrial thickness, as assessed by transvaginal ultrasonography.2
Tamoxifen, a triphenylethylene selective estrogen receptor modulator, is indicated for adjuvant treatment of breast cancer5 and for reduction in breast cancer incidence in high-risk women.6 An association between long-term tamoxifen therapy and increased risk of endometrial cancer was reported initially in 19857 and was confirmed by clinical trials.6,8 Uterine monitoring in postmenopausal women found that short-term tamoxifen use caused endometrial stimulation, including hyperplasia,9 and increased endometrial thickness10 as early as 6 months after commencing therapy.11 These estrogen-agonist uterine effects that can occur with tamoxifen therapy were observed also with unopposed estrogen, which in short-term use was associated with endometrial hyperplasia12 and in long-term use was associated with endometrial cancer.13–16 Current estrogen replacement regimens include sequential or concomitant progestin administration to protect against endometrial stimulation.12,17 Combined estrogen-progestin regimens are used to alleviate perimenopausal symptoms and to prevent postmenopausal osteoporosis.18,19
To confirm that new estrogen-progestin drug regimens do not induce endometrial hyperplasia, Food and Drug Administration guidelines recommend uterine safety monitoring by endometrial biopsy and routine transvaginal ultrasound, with an unopposed estrogen treatment arm as a positive control.20 When transvaginal ultrasound findings are not conclusive, saline-infusion sonohysterography can elucidate the etiology of endometrial thickening.21 For example, women taking tamoxifen who had an unusual ultrasonographic appearance of the uterus were found by saline-infusion sonohysterography to have adenomyomatous-like changes in the proximal myometrium.22 Because of uterine effects previously observed with unopposed estrogen and tamoxifen, the present study systematically evaluated the uterine safety of raloxifene in postmenopausal women. The surveillance algorithm involved masked endometrial sampling, transvaginal ultrasonography, and saline-infusion sonohysterography to obtain a global view of the endometrial cavity, with focal abnormalities to be followed up by hysteros-copy and guided biopsy.23
The primary objective of this trial was to provide a detailed analysis of the uterine effects of raloxifene in a general population of postmenopausal women with a normal endometrium at baseline, defined by endometrial biopsy, and an endometrial thickness of 5.0 mm or less, determined by transvaginal ultrasonography.
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Materials and Methods |
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Healthy women with a normal uterus, 47–60 years of age, 2 to 8 years postmenopause, with serum estradiol of 73 pmol/L (20 pg/mL) or less, and lumbar spine bone mineral density (BMD) measurements (average of L1 to L4) between 2 standard deviations (SD) above and 2.5 SD below the mean peak lumbar spine BMD for premenopausal women, inclusive, were eligible. Exclusion criteria included uterine bleeding of unknown etiology or intolerable postmenopausal symptoms requiring estrogen therapy; body mass index below 18 kg/m2 or above 31 kg/m2; history of cancer within the 5 years before consideration for study entry; history of deep venous thromboembolic disease; or use of cortico-steroids, estrogen, or progestin within 6 months before beginning the study. In addition, women who had abnormal ovaries or endometrial thickness greater than 5.0 mm as determined by transvaginal ultrasonography; any significant pelvic pathology, as determined by Papanicolaou screening smear, pelvic transvaginal ultrasonography, saline-infusion sonohysterography, or endometrial biopsy; or in whom the uterine cavity could not be evaluated were ineligible for the study. Investigators obtained Institutional Review Board approval. Women signed a written informed consent document before entering the study.
Endometrial biopsies were obtained after the ultrasound studies at baseline and every 6 months, using a nondirected endometrial sampling technique. Endometrial samples were evaluated according to morphologic criteria of Blaustein,24 according to the Food and Drug Administration Hormone Replacement Therapy Working Group guidelines.20 Samples were read independently by two pathologists masked to therapy group and temporal ordering. Samples were sent to a third, independent, masked pathologist for a final diagnosis when diagnostic differences occurred between the two readers. Women in whom hyperplasia developed at any visit were discontinued from their assigned therapy and appropriately treated and monitored.
A protocol for systematic evaluation of the uterus was developed for transvaginal ultrasound measurements of the corpus and endometrial thickness, with and without saline infusion. Researchers from all study sites were trained in hands-on sessions with live models and given detailed training videotapes and illustrated training manuals to ensure uniform technique. Ultrasound equipment with endovaginal probes for B-mode, at least 5 MHz, were used, and the endometrium was measured in tenths of a millimeter. The technique consisted of identification of the uterus in the midsagittal plane, based on the cervical canal, according to the previously described protocols.21,25 Uterine diameters were measured in the longitudinal (D1), transverse (D2), and anterior-posterior (D3) planes,10 and total uterine volume (in cm3) was calculated as (D1 x D2 x D3)/2. Ovaries were scanned in two planes and any abnormalities were measured. Transvaginal ultrasonography was done at baseline and every 3 months. Saline-infusion sonohysterography, which involved ultrasound with saline infusion while scanning, was done at baseline and every 6 months according to the method of Parsons et al.26 The transvaginal ultrasonography and saline-infusion sonohysterography procedures were videotaped and sent to the central reader (AKP), who was masked to therapy and made the final diagnosis.
Subjects who had either endometrial thickness greater than 5.0 mm, as determined by transvaginal ultrasonography, or uterine bleeding after 3 months underwent additional gynecologic surveillance according to a predetermined algorithm,23 that included saline-infusion sonohysterography (Figure 1
). When saline-infusion sonohysterography detected a single-layer endometrial thickness of more than 3 mm or a focal abnormality, then directed biopsy with hysterography was indicated. If the endometrium was uniformly thickened, as detected by saline-infusion sonohysterography, then a nondirected biopsy was done. Adverse events were collected before study procedures were performed, at baseline, and at 3-month intervals.
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For categoric data, Fisher exact test and the 
2 test were used for therapy comparisons. A P value is provided whenever the total incidence in the category is five or more. Fisher exact test was used to analyze the incidence of the primary safety end point, endometrial hyperplasia, with pairwise comparisons between the therapy groups whenever the overall therapy effect was significant at the .05 two-sided 
level. Adverse events were analyzed using the 2 test and Fisher exact test.
For continuous data, an analysis of variance model was used to evaluate therapy differences, with fixed effects for therapy, investigator, and therapy-by-investigator interaction. The therapy-by-investigator interaction term was eventually dropped from the model because the interaction was rarely significant at the .10 level of significance, and even when significant was never qualitative. The baseline-to-end-point changes in continuous safety measures, such as endometrial thickness, were analyzed using analysis of variance. Least-square means were used to test each pairwise therapy comparison at the .05 two-sided level of significance. Paired t tests were used to analyze changes over time within each therapy group. Therapy differences in baseline subject characteristics were assessed using the 2 test and analysis of variance, as appropriate.
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Results |
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). The histologic categories of inadequate tissue, surface endometrium, or inactive or atrophic tissue were defined as normal benign postmenopausal endometrium.24 There were no cases of endometrial hyperplasia at baseline. In the 88 women in the estrogen group who had paired biopsies, 23 cases (26.1%) of endometrial hyperplasia were found (P < .001, Table 2). Seven (30.4%) of these 23 cases were diagnosed by 3 months into the study, and a total of 12 cases (52.2%) were diagnosed by 6 months. In two (2.1%) of the 94 women in the placebo group who had paired biopsies, hyperplasia was diagnosed at the 12-month visit. Seventeen biopsies were diagnosed as proliferative tissue at baseline. Of these biopsies, six of seven in the placebo group, two of two in the raloxifene 60 mg/day group, two of three in the raloxifene 150 mg/day group, and one of two in the estrogen group were diagnosed as normal benign postmenopausal endometrium at end point. None of the other three women whose baseline biopsies were diagnosed as proliferative tissue had biopsies that progressed to hyperplasia at end point. Proliferative tissue was diagnosed at end point in two (2.1%) women in the placebo group, three (3.6%) in the raloxifene 60 mg/day group, and 35 (39.8%) in the estrogen group (P < .001). None of the women in the raloxifene 150 mg/day group had proliferative tissue at end point. When the 176 paired biopsies in both raloxifene groups were pooled, the combined incidence of proliferative tissue was 1.7%. All five women in the placebo and the raloxifene 60 mg/day groups who had proliferative tissue at end point had a body mass index greater than 29 kg/m2.
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). All except three of these polyps were atrophic or functional. Two polyps in the estrogen group and one polyp in the placebo group were reported as hyperplastic. None of the polyps were associated with concurrent endometrial hyperplasia.
Mean double-layer endometrial thickness, determined by transvaginal ultrasonography, did not differ significantly among therapy groups at baseline (Table 1). At end point, the mean endometrial thickness was not changed significantly from baseline in the placebo, raloxifene 60 mg/day, and raloxifene 150 mg/day groups, and the mean baseline-to-end-point changes were not significantly different among these three groups (Figure 3A, Table 3). In the raloxifene 60 mg/day group, there was a significant but transient increase in mean endometrial thickness of 0.4 mm from baseline at 3 and 6 months, which was not seen at 9 or 12 months of treatment. The mean endometrial thickness in the estrogen group increased by 4.4 mm at 3 months and increased by a total of 5.5 mm at end point (P < .001, Figure 3A). The mean baseline-to-end-point change in endometrial thickness in the estrogen group was significantly different from those of the other groups at all time points measured (P < .001, for all three comparisons, Table 3). An increase in endometrial thickness to over 5.0 mm at end point was observed in 6.0% of women in the placebo group, 4.7% in the raloxifene 60 mg/day group, 4.2% in the raloxifene 150 mg/day group, and 70.3% in the estrogen group.
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), but the mean baseline-to-end-point changes were significantly different among the four therapy groups (P < .001 for all three parameters, Table 3). In the placebo group and both raloxifene groups at end point, the mean total endometrial thickness was not significantly changed from baseline and was not significantly different among these three groups (Figure 3B). However, end-point endometrial thickness in the estrogen group increased from baseline by 2.4 mm (P < .001) in the anterior wall and 2.3 mm (P < .001) in the posterior wall (Table 3). These increases were significantly different from the other groups (P < .001, for all three comparisons at both time points; Figure 3).
Uterine volume, calculated from the transvaginal ultrasonography measurements, was not statistically different between therapy groups at baseline (Table 1). At end point, uterine volume significantly decreased from baseline in the placebo (P = .007) and raloxifene 150 mg/day groups (P = .038, Figure 4). At end point, these changes were not significantly different among the placebo and both raloxifene groups (Table 3). Uterine volume in the estrogen group had increased at end point by 22 cm3 (66% from baseline), which was significantly different from baseline and from the other groups at all time points measured (P < .001 for all comparisons; Table 3, Figure 4).
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< .05). Among the 415 women, at least one hot flash incident was reported by nine women (8.3%) in the placebo group, 10 (9.9%) in the raloxifene 60 mg/day group, 13 (12.4%) in the raloxifene 150 mg/day group, and five (5.0%) in the estrogen group. The incidences of hot flashes were not significantly different among the therapy groups.
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Discussion |
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Endometrial biopsy results indicated that hyperplasia developed in no woman in either raloxifene group. Hyperplasia was diagnosed in 26% of women in the estrogen group at 1 year, which is comparable to the 20% incidence in another study of unopposed estrogen.17 A lower dose (0.3 mg/day) of unopposed esterified estrogen induced less hyperplasia than a 0.625 mg/day dose, and the degree of endometrial proliferation advanced from mild to moderate within 6 months compared with placebo.28 In the present study, the incidence of proliferative endometrium in the estrogen group was higher, whereas that in the raloxifene groups was indistinguishable from the placebo group throughout the study. Therefore, raloxifene treatment did not produce uterine stimulation as determined by endometrial biopsy. These results extend the findings of a placebo- and estrogen-controlled 8-week study with raloxifene evaluated at doses of up to 600 mg/day.27 Mean endometrial thickness, as measured by transvaginal ultrasonography, was not different between placebo and either raloxifene group at the 12-month endpoint. There was no difference in endometrial thickness from baseline to end point in both raloxifene groups. The minimal (0.4 mm) changes in the raloxifene 60 mg/day group at 3 and 6 months were not considered clinically significant, as they were not associated with any concurrent changes detected by endometrial biopsy and were not found in women with outlying values. Also, the mean total endometrial thickness in the raloxifene 60 mg/day group, determined by saline-infusion sonohysterography, did not confirm the transvaginal ultrasonography observations at 6 months. Mean total endometrial thickness, as determined by saline-infusion sonohysterography, was not different within or among the placebo and both raloxifene groups at any time point. In the estrogen group, however, the mean change in endometrial thickness, as determined by saline-infusion sonohysterography, was increased from baseline and increased from that in the other three groups. The increased endometrial thickness in the estrogen group occurred in conjunction with changes in endometrial histologic characteristics. Systematic uterine evaluation in the present study confirmed the findings of previous raloxifene studies of longer duration. No increase in mean endometrial thickness was observed by transvaginal ultrasonography in a 2-year study with 60 and 150 mg/day doses of raloxifene.2 The present study also demonstrated that unopposed estrogen increased uterine volume, which had been previously reported for tamoxifen.10 Raloxifene did not increase uterine volume.
Saline-infusion sonohysterography is useful for determining endometrial thickness when diagnosis by transvaginal ultrasonography is inconclusive.21 Some patients taking tamoxifen have an unusual sonolucent appearance in the endometrium as observed by transvaginal ultrasonography. When the image was enhanced with saline-infusion sonohysterography, the endometrial appearance was found to result from adenomyomatous-like changes in the proximal myometrium or endometrial basalis, but not superficial endometrial thickening.22,29 Saline-infusion sonohysterography is also valuable for elucidating focal abnormalities, such as endometrial polyps.21 Compared with untreated patients, tamoxifen-treated postmenopausal patients with breast cancer had increased endometrial thickness and uterine volume and a higher incidence of endometrial proliferation, hyperplasia, endometrial polyps, and uterine fibroids.30–32 Tamoxifen treatment also had similar effects in healthy postmenopausal women.10 The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial P-1 determined that tamoxifen use in women over age 50 years was associated with an increased relative risk of 4.0 for invasive and in situ endometrial cancer. An increased incidence of invasive endometrial cancer was observed early in the follow-up period in the P-1 trial.6 Tamoxifen was used as adjuvant therapy for breast cancer for many years by women with uteri, without concomitant assessment of endometrial safety, before an unexpected relationship between tamoxifen use and endometrial cancer was suspected.33,34 If prospective uterine safety monitoring had been done, an association between the early endometrial changes observed in patients taking tamoxifen and endometrial cancer risk might have been suspected earlier.
A prospective study that assesses the early endometrial changes with selective estrogen receptor modulators might indicate long-term uterine safety. In contrast to the previous findings for tamoxifen, the incidence of focal abnormalities in the raloxifene groups did not differ from that in the placebo group in the present study. The incidence of endometrial polyps, confirmed by guided biopsy, was not different between the placebo and both raloxifene groups. There were no differences between treatment groups in the reported occurrences of adenomyomatous-like changes in the proximal myometrium, as detected by saline-infusion sonohysterography, or in cystic ovarian changes or endometrial fluid, as detected by transvaginal ultrasonography. Although tamoxifen and raloxifene are both selective estrogen receptor modulators, they have widely different effects on the uterus. Those observations reinforce the need to evaluate each selective estrogen receptor modulator extensively and individually and to avoid extrapolating the uterine effects from one drug to another.
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Footnotes |
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Financial Disclosure
Authors Scheele, Rajagopalan, and Wilkie are or have been employees of and hold stock in Eli Lilly and Co. Authors Goldstein, Parsons, and Walsh received research funding from Eli Lilly and Co.
Received April 5, 1999. Received in revised form June 21, 1999. Accepted July 1, 1999.
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2. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641–7.
3. Cummings S, Eckert S, Krueger K, Grady D, Powles T, Cauley J, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999;281:2189–97.
4. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445–51.
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24. Kurman RJ, Norris HJ. Endometrial hyperplasia and related cellular changes. In: Kurman RJ, ed. Blaustein’s pathology of the female genital tract. 4th ed. New York: Springer-Verlag; 1994: 411–27.
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O. Johnell, W. H. Scheele, Y. Lu, J.-Y. Reginster, A. G. Need, and E. Seeman Additive Effects of Raloxifene and Alendronate on Bone Density and Biochemical Markers of Bone Remodeling in Postmenopausal Women with Osteoporosis J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 985 - 992. [Abstract] [Full Text] [PDF]
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 V. C. Jordan, S. Gapstur, and M. Morrow Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease J Natl Cancer Inst, October 3, 2001; 93(19): 1449 - 1457. [Abstract] [Full Text] [PDF]
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 S. H.-J. Hsu, W.-C. Cheng, M.-W. Jang, and K.-S. Tsai Effects of Long-Term Use of Raloxifene, a Selective Estrogen Receptor Modulator, on Thyroid Function Test Profiles Clin. Chem., October 1, 2001; 47(10): 1865 - 1867. [Full Text] [PDF]
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S. R. Goldstein, P. Neven, L. Zhou, Y. L. Taylor, A. V. Ciaccia, and L. Plouffe Jr Raloxifene Effect on Frequency of Surgery for Pelvic Floor Relaxation Obstet. Gynecol., July 1, 2001; 98(1): 91 - 96. [Abstract] [Full Text] [PDF]
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M. E. Lippman, K. A. Krueger, S. Eckert, A. Sashegyi, E. L. Walls, S. Jamal, J. A. Cauley, and S. R. Cummings Indicators of Lifetime Estrogen Exposure: Effect on Breast Cancer Incidence and Interaction With Raloxifene Therapy in the Multiple Outcomes of Raloxifene Evaluation Study Participants J. Clin. Oncol., June 15, 2001; 19(12): 3111 - 3116. [Abstract] [Full Text] [PDF]
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 J. M. Cline, G. Soderqvist, T. C. Register, J. K. Williams, M. R. Adams, and B. Von Schoultz Assessment of Hormonally Active Agents in the Reproductive Tract of Female Nonhuman Primates Toxicol Pathol, January 1, 2001; 29(1): 84 - 90. [Abstract] [PDF]
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 J. C. Stevenson, M. Flather, P. Collins, N. P. Assefi, C. S. Rhoads, M. Bassan, P. W. Anderson, E. Moscarelli, D. M. Herrington, D. Waters, et al. Coronary Heart Disease in Women N. Engl. J. Med., December 21, 2000; 343(25): 1891 - 1894. [Full Text]
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 D. B. Muchmore Raloxifene: A Selective Estrogen Receptor Modulator (SERM) with Multiple Target System Effects Oncologist, October 1, 2000; 5(5): 388 - 392. [Abstract] [Full Text]
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R. STRICKLER, D. W. STOVALL, D. MERRITT, W. SHEN, M. WONG, and S. L. SILFEN Raloxifene and Estrogen Effects on Quality of Life in Healthy Postmenopausal Women: A Placebo-Controlled Randomized Trial Obstet. Gynecol., September 1, 2000; 96(3): 359 - 365. [Abstract] [Full Text] [PDF]
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 L. louffe Jr. Selective Estrogen Receptor Modulators (SERMs) in Clinical Practice Reproductive Sciences, January 1, 2000; 7(1_suppl): S38 - S46. [Abstract] [PDF]
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5.0 mm) and who were screened from a general population of 981 postmenopausal women.
