Of the 1,008 randomized women who participated in the core phase, 495 were randomly assigned to raloxifene and 513 received continuous combined estrogen plus progestin therapy. Of the total population, 334 cases had 1 or several findings making them eligible for individual review in the adjudication process, 73 (14.7%) from the raloxifene group and 261 (50.9%) from the continuous combined estrogen plus progestin therapy group (P < .001). A total of 274 uterine diagnostic observations that were classified other than “normal” were found in 239 patients. Thirty-three patients (6 taking raloxifene and 27 taking continuous combined estrogen plus progestin therapy) had 2 diagnoses, and 1 patient on continuous combined estrogen plus progestin therapy had 3 diagnoses.
The absolute incidences, percentages, and between-group differences for the individual diagnostic categories during the core and extension phase of the study are listed in Table 4. The number of patients with premalignant/malignant findings was 1 in the raloxifene arm and 3 in the continuous combined estrogen plus progestin therapy treatment arm (P = .625). In contrast, the number of cases with findings of benign endometrial proliferation, polyps, and cystic atrophy was significantly higher in women taking continuous combined estrogen plus progestin therapy than in women on raloxifene (P < .001, P = .048, P < .001, respectively; Table 4). Although the number of cases classified as “unclear” did not exceed 1% in either group, the frequency of inadequate follow-up was much higher in the continuous combined estrogen plus progestin therapy group (11.9% versus 2.4%, P < .001).
Treatment-emergent intrauterine fluid was detected in 17 (4.0%) of evaluatable patients on raloxifene and in 28 (6.6%) of all evaluatable patients on continuous combined estrogen plus progestin therapy (P = .094).
We performed an additional exploratory subgroup analysis, defined as post hoc, of all patients who reported any bleeding or spotting during the core phase with respect to their adjudicated diagnoses. The results are presented in Table 5. Of the 33 patients who bled on raloxifene, only 2 cases had treatment-emergent pathologic uterine findings (1 polyp and 1 inflammatory change), whereas all others did not require adjudication, were adjudicated as “normal,” or had preexisting signs of benign endometrial stimulation. In contrast, of the 275 patients who bled on continuous combined estrogen plus progestin therapy, 204 required adjudication, and much larger numbers than on raloxifene were diagnosed with treatment-emergent benign proliferation (n = 38), polyps (n = 16), or cystic atrophy (n = 13). Of the total number of treatment-emergent premalignant/malignant findings (n = 4) only 2 (both from the continuous combined estrogen plus progestin therapy group) were associated with repeated bleeding, whereas the other 2 cases remained asymptomatic and were detected only because of the protocol-required transvaginal ultrasonography examinations after 6 months of treatment.
Of the 347 women who continued in the extension phase of the study, 183 were taking raloxifene and 164 received continuous combined estrogen plus progestin therapy. In total, 177 required adjudication: 74 (40.4%) from the raloxifene group and 103 (62.8%) from the continuous combined estrogen plus progestin therapy group. The absolute incidences, percentages, and between-group differences for the individual diagnostic categories from the extension phase are shown in Table 4. No premalignancies or malignancies were described in the extension subgroup. Statistically significant differences were found in 2 diagnostic categories, both favoring raloxifene. The rates of patients classified as “normal by transvaginal ultrasonography” (ie, patients with repeated bleeding/spotting but no other abnormal findings) and of patients with inadequate follow-up were higher (P < .001) in the continuous combined estrogen plus progestin therapy group.
The results of the present study have shown that a “European” continuous combined estrogen plus progestin therapy formulation (17β-E2 and norethisterone acetate) is associated with a higher rate of benign endometrial pathology, specifically cystic atrophy, endometrial proliferation, and endometrial polyps than raloxifene. This study also shows that neither this continuous combined estrogen plus progestin therapy regimen nor raloxifene are associated with (pre-)malignant endometrial pathology. However, the need for gynecological follow-up and safety testing predefined in the study protocol in women using either regimen for the treatment or prevention of postmenopausal health risks was significantly greater in those on continuous combined estrogen plus progestin therapy, mainly because of abnormal vaginal bleeding.
The results with raloxifene are consistent with findings from other trials. In several previous studies, raloxifene was indistinguishable from placebo regarding the rate of uterine bleeding and endometrial thickness.21,24 Furthermore, the frequency of bleeding, endometrial thickness, and uterine volume remained stable (compared with baseline) on raloxifene while increasing with cyclic or continuous combined estrogen plus progestin therapy.21,25 Similar results were found in the present trial with 17β-E2 and norethisterone acetate instead of the treatment regimens consisting mostly of conjugated equine estrogens and medroxyprogesterone acetate in the previous studies and have been published previously.22 The trial by Fugère et al25 also reported a higher incidence in benign endometrial proliferation in the continuous combined estrogen plus progestin therapy group, but, in contrast to our findings, no polyps or cystic atrophy nor any therapy-related difference in them. This may be the result of the much smaller size of the Fugère study (136 versus 1,008 patients). Goldstein et al26 reported similar rates in polyps among women taking raloxifene, unopposed conjugated equine estrogens, or placebo and did not mention any cases of cystic atrophy in his study that was, however, also much smaller than our study. Thus, the finding of increased endometrial polyps and cystic atrophy in continuous combined estrogen plus progestin therapy, compared with raloxifene, is described here for the first time. Kliogest’s feature of inducing in a time-related manner endometrial atrophy in up to 50% of those using it for up to 5 years has recently been published.27 Unfortunately, in that study, the longest follow-up uterine safety study with Kliogest to date, the rate of endometrial polyps was not reported because the investigators only evaluated histology from blind endometrial sampling.27 In our opinion, cystic atrophy may induce vaginal spotting/bleeding because it leads to withdrawal of stromal support for blood vessels, which, in turn, causes dilatation and extravasation of blood. Several authors28,29 reject the hypothesis that estrogen plus progestin therapy is a risk factor for endometrial polyps. Some of the polyps in our study may have been picked up through detection bias but another hypothesis is that raloxifene protects against endometrial polyps. The difference in cystic atrophy is somewhat surprising because cystic atrophy usually is associated with tamoxifen, a first-generation selective estrogen receptor modulator, rather than with estrogen plus progestin therapy.30 We therefore expected, before our study was unblinded, that the majority of our cases with cystic atrophy would be in the raloxifene group.
The small number of premalignant/malignant uterine bioptic findings that emerged during treatment and the absence of a statistically significant between-group difference in their rate suggest that there are no treatment-specific differences with respect to the occurrence of malignancies during the first year. This should reassure the patient and her physician when dealing with abnormal bleeding.
The limitations of this study must be acknowledged. First, there was no placebo arm to compare uterine safety of raloxifene with a nontreated group, but several placebo-controlled trials have already been performed, and the results have been reported.20,21,24–26 Second, lower-dose formulations of continuous combined estrogen plus progestin therapy, which are less likely to have stimulating uterine effects, have become available in the meantime, but at the time of the initiation of the study, the regimen of Kliogest was the most widely used continuous combined estrogen plus progestin therapy and the only continuous combined formulation of E2 and norethisterone acetate that was available throughout Europe. Third, for some of the more rarely found diagnostic categories, notably the category of premalignant/malignant findings, the statistical power of the study was inadequate because of its sample size and limited duration. Finally, D&C is not an ideal method for the histological explanation of endometrial abnormalities, especially when these are focal. However, because D&C was performed only at the few centers where saline-infused sonohysterography and hysteroscopy with guided biopsy were not available, only 17 of 334 patients underwent D&C. Because of this small proportion (approximately 5%), the D&C results are unlikely to have led to any major distortions in our results.
In conclusion, this study demonstrates that raloxifene is associated with less endometrial stimulation than continuous combined estrogen plus progestin therapy and lends further indirect support to the results from previous, placebo-controlled trials showing that raloxifene has no stimulatory effect on the endometrium. Changes as observed with tamoxifen were rarely seen in the 1 year during which patients were on treatment; specifically, the incidence of cystic atrophy, a finding that is often associated with tamoxifen and therefore possibly related to selective estrogen receptor modulators, was observed 4 times more frequently with continuous combined estrogen plus progestin therapy than with raloxifene in this study. Although the rate of premalignant/malignant findings did not differ between the treatment arms, endometrial polyps were twice as frequent with continuous combined estrogen plus progestin therapy than with raloxifene.
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Investigators for the EURALOX 1 Trial:
Belgium: Dr. Patrick Neven, Algemene Kliniek St. Jan, Brussels (Principal Investigator); Dr. Mireille Smets, Cliniques Universitaires Saint-Luc, Brussels; Dr. Rudy Gevers, Akademisch Ziekenhuis VUB-Jette, Brussels; Dr. Guido Vanderick, Algemene Kliniek St.-Jan, Brussels; Dr. Frederic van den Brul, CHU Sart Tilman, Liège; Prof. Herman Depypere, UZ-Gent; Denmark: Dr. Sven Skouby, Frederiksberg Hospital, Frederiksberg; Dr. Anette Peen, Speciallaegernes Hus, Aarhus; Dr. Lars Andersen, Sygehus Hillerod; Dr. Torben Philipsen, Centralsygehus Holbaek; Dr. Birger Moller, Universitetshospital Odense; Dr. Erik Poulsen, Odense; Dr. Lars-Olof Abrahamsson, Hvidovre; Dr. Anne Jessen, Sonderborg; Prof. Bent Ottesen, Hvidovre Hospital, Hvidovre; Dr. Jens Lyndrup, Amtssygenhus, Roskilde; Finland: Prof. Aila Tiitinen, Helsingin Yliopistollinen Keskussairaala, Helsinki; Prof. Tuula Salmi, Turun Yliopistollinen Keskussairaala, Turku; Prof. Risto Tuimala, Tampereen Yliopistollinen Keskussairaala, Tampere; Prof. Ulla Puistola, Oulun Yliopistollinen Keskussairaala, Oulu; Dr. Jukka Puolakka, Keski-suomen Keskussairaala, Jyväskylä; Dr. Tarja Jarvi, Hemo Ov, Laakariasema, Lahti; Dr. Pentti Kilkku, Torilinnan Laakariasema, Pori; Dr. Marjo Tuppurainen, Kuopion Yliopistollinen Keskussairaala, Kuopio; France: Dr. Marc Levrier, Talence; Dr. Monique Commenges, Centre Hospitalier Pellegrin Tripode, Bordeaux; Dr. Veronique Kerlo, Nantes; Dr. Lucien Chaby, Centre de Santé Jack Senet, Paris; Dr. Michèle Scheffler; Nancy; Dr. Veronique Pascal, Hôpital Brabois, Vandoeuvre Nancy; Prof. Patrick Madelenat, Hôpital Bichat, Paris; Dr. Charles Nahmanovici, Nice; Dr. Francoise Mousteou, Cagnes-sur-Mer; Dr. Dominique Crestinu, Paris; Dr. Dominique Wiel-Masson, Chartres; Dr. Alain Audebert, Bordeaux; Prof. Gerard Mage, Hôtel Dieu, Clermont-Ferrand; Dr. Aliette Siboni-Frisch, Toulouse; Dr. Marie-Hélène Cayrol, Clinique St. Jean de Languedoc, Toulouse; Dr. Isabelle Zordan-Ducasse, Toulouse; Dr. Martine Gelas, Lyon; Dr. Pascale Mirakian, Clinique Montplaisir, Lyon; Dr. Bruno Mazenod, Hôpital de l’Antiquaille, Lyon; Dr. Colette Ferrand-Desneiges, Rouen; Dr. Martine Pollack, Grenoble; Dr. Nicole Douay, Villeneuve d’Ascq; Dr. Katty Ardaens, Seclin; Dr. Francis Sailly, Tourcoing; Dr. Martine Perdrix, Clinique Médical Mgen, Lyon; Greece: Prof. George Creatsas, Aretaieio Hospital, Athens; Ireland: Dr. Maire Milner, Rotunda Hospital, Dublin; Prof. John Bonnar, St. James’ Hospital, Dublin; Israel: Prof. Zion Ben-Rafael, Rabin Medical Center, Petah Tiqva; Dr. Yair Frenkel, Chaim Sheba Medical Center, Tel-Hashomer; Dr. Nahman Eckstein, Ichilov Hospital, Tel-Aviv; Dr. Eitan Pe’er, Rambam Medical Center, Haifa; Italy: Prof. Carlo Campagnoli, Ospedale Ginecologico S. Anna, Torino; Prof. Pierluigi Benedetti-Panici, Libero Istituto Universitario, Roma; Prof. Carmine Nappi, Universitá Federico II, Napoli; Prof. Annibale Volpe, Policlinico Universitario, Modena; Prof. Alberto Bacchi, Clinica Ostetrica e Ginecologica dell′Universitá, Parma; Prof. Domenico de Aloysio, Clinica Ginecologica ed Ostetrica dell’Universitá, Bologna; Prof. Vincenzo Giambanco, Ospedale Civico E. Benfratelli, Palermo; Prof. Costante Donati Sarti, Policlinico Monteluce, Perugia; Prof. Sergio Schonauer, Policlinico Universitario, Bari; Prof. Secondo Guaschino, Istituto Burlo Garofolo, Trieste; Netherlands: Dr. J. Schram, Drechtsteden Ziekenhuis, Zwijndrecht; Dr. W. Stroobants, St. Jozef Ziekenhuis, Kerkrade; Dr. H. The, St. Gemini Ziekenhuis, Den Helder; Dr. A. Broekman, Twesteeden Ziekenhuis, Waalwijk; Dr. T. M. Hameeteman; St. Antonius Ziekenhuis, Nieuwegein; Dr. Beth Morrel, Ikazia Ziekenhuis, Rotterdam; Dr. Tjeerd D Ypma, Scheper Ziekenhuis, Emmen; Dr. Leen Pijpers, Albert Schweitzer Ziekenhuis, Dordrecht; Dr. Lodewijk J Bosch van Drakenstein, Flevoziekenhuis, Almere; Norway: Dr. B. Eriksen, Haugesund Gyn Klinikk, Haugesund; Dr. Hans Ejner Ipsen, Volvat Legesenter, Alesund; Dr. Terje Soerdal, Spesialistlegesenteret, Trondheim; Dr. Gunnar Nordland, Faber Swensson & Nordland, Kristiansund; Dr. Tore Lunde, Larvik; Dr. Randi Simes Dugal, Sandefjord; Dr. Oeyvin Skarra, Osteoporoselaboratoriet A.S., Oslo; Dr. Tor Loevset, Bergen; Dr. Unn Baerug, Halden; Poland: Dr. Romuald Debski, Klinika Ginekologii Poloznictwa Cmkp, Warszawa; Prof. Alina Warenik-Szymankiewicz, Katedra Endokrinologii Ginekologicznej, Poznan; Dr. Violetta Skrzypulec-Ciszek, IV. Katedra i Klinika Poloznictwa i Ginekologii, Tychy; Dr. Tomasz Rechberger, II Katedra Poloznictwa i Chorób Kobiecych, Lublin; Prof. Tomasz Pertynski, Oddzial Kliniczny Chorób Menopausy; Lódz; Prof. Jerzy Mielnik, I Klinika Poloznictwa i Ginekologii A.M., Gdansk; Prof. Stanislaw Rozewicki, Klinika Ginekologii, Szczecin; Portugal: Dr. Fernanda Aguas, Maternidade Bissaya Barreto, Coimbra; Dr. Ana Fatela, Maternidade Dr. Alfredo da Costa, Lisboa; Prof. Madalena Botelho, Hospital de Santa Maria, Lisboa; Dr. Isabel Amaral, Hospital Nossa Senhora do Rosário, Barriero; Dr. Olga Viseu, Hospital Distrital, Faro; Prof. Martinez Oliveira, Hospital de Sao Joao, Porto; Dr. Ana Pinho, Garcia da Orta, Almada; Prof. Henrique Oliveira, Hospitais da Universidade, Coimbra; Romania: Prof. Bogdan Marinescu, Clinical Hosptial of Obstetrics and Gynecology, Bucuresti; Prof. Decebal Hudita, Spitalul Clinic Cantacuzino, Bucuresti; Prof. Florin Stamatian, Clinic of Gynecology Dr. Stanca, Cluj; South Africa: Dr. F. Grobler, Medfem Clinic, Sandton; Dr. Pierre Davis, Little Company of Mary Medical Centre, Pretoria; Dr. Tobie Devilliers, Panorama Medical Clinic, Cape Town; Spain: Dr. Camil Castelo-Branco, Hospital Clinic I Provincial, Barcelona; Dr. Montserrat Manubens, Institut Dexeus, Barcelona; Dr. Joaquin Calaf, Hospital Santa Creu i Sant Pau, Barcelona; Dr. Albert Cabero, Ciutat Sanitaria de la Vall D’Hebron, Barcelona; Dr. José L. Duenas-Diez, Hospital Universitario Virgen Macarena, Sevilla; Dr. Antonio Cano, Hospital Clínico Universitario, Valencia; Sweden: Prof. Torbjörn Bäckström, Norrlands Universitetssjukhus, Umea; Dr. Staffan Nilsson, Falu Lasarett, Falun; Dr. Lars-Ake Mattsson, Sahlgrenska Univ/Östra, Göteborg; Dr. Göran Berg, Universitetssjukhuset, Linköping; Prof. Britt Marie Landgren, Karolinska Sjukhuset, Stockholm; Prof. Göran Samsioe, Universitetssjukhuset, Lund; Switzerland: Prof. Paul J. Keller, Universitätsspital, Zürich; Dr. Christian de Geyter, Kantonsspital, Basel; Prof. Martin Birkhauser, Inselspital, Bern; Turkey: Prof. Cihat Unlu, University Department of Gynecology and Obstetrics, Ankara; Prof. Erdogan Ertungealp, I.U. Cerrahpasa Medical Faculty, Istanbul; Prof. Mithat Erenus, Marmara University, Istanbul; Prof. Abdullah Turfanda, I.U. Istanbul Medical Faculty, Istanbul; United Kingdom: Dr. M. Stone, Llandough Hospital, South Glamorgan; Dr. Timothy Hillard, Poole Hospital NHS Trust, Poole; Dr. Michael Cust, City General Hosptial, Derby; Dr. John B. Paling, Nuffield Hospital, Birmingham; Dr. S. H. Taylor, Synexus Ltd. Clinical Research Unit, Chorley.