Obstetrics & Gynecology:
Uterine Effects of Estrogen Plus Progestin Therapy and Raloxifene: Adjudicated Results From the EURALOX Study
Neven, Patrick MD, PhD*; Quail, Deborah BSc†; Lévrier, Marc MD‡; Aguas, Fernanda MD§; Thé, Hok Sien MD¶; De Geyter, Christian MD, PhD∥; Glant, Michael D. MD**; Beck, Heike MD††; Bosio-LeGoux, Brigitte MD†; Schmitt, Henri MD†; Hottgenroth, Antje PhD†; Nickelsen, Thomas MD, PhD†
From the *Department of Gynaecological Oncology, Univesity of Leuven, Leuven, Belgium; †Eli Lilly and Company, Bad, Homburg, Germany; ‡Collège de Gynecologie de Bordeaux et du Sud-Ouest, Talence, France; §Maternidade Bissaya Barreto, Coimbra, Portugal; ¶St. Gemini Ziekenhuis, Den Helder, The Netherlands; ∥Kantonsspital Basel, Switzerland; **Diagnostic Cytology Laboratories, Indianapolis, Indiana; and ††Gynäkologische Gemeinschaftspraxis, Offenbach, Germany.
The authors thank Mr. Tero Laulajainen, BSc, for his help in the central study coordination.
For a list of the investigators of the EURALOX 1 trial, see the Appendix.
Financial Disclosure This clinical trial was supported by Eli Lilly & Company. Drs. Quail, Bosio-LeGoux, Schmitt, Hottgenroth, and Nickelsen are employees of Eli Lilly Research Laboratories and own Eli Lilly stock. Drs. Neven and Glant have received consultant and speaker honoraria from Eli Lilly & Company. Drs. Lévrier, Aguas, Thé, de Geyter, and Beck have received investigator honoraria for their work on the trial.
Address reprint requests to: Patrick Neven, MD, PhD, Department of Gynaecological Oncology, UZ-Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; e-mail: Patrick.email@example.com.
Received May 22, 2003. Received in revised form January 8, 2004. Accepted January 15, 2004.
OBJECTIVE: To compare the incident rate of abnormal endometrial findings in postmenopausal women receiving treatment with either 60 mg of raloxifene or a continuous combined estrogen plus progestin therapy containing 2 mg of 17β-estradiol plus 1 mg of norethisterone acetate for a duration of up to 12 months.
METHODS: One thousand eight asymptomatic postmenopausal women with osteoporosis or cardiovascular risk factors with an endometrial thickness of less than 5 mm at baseline participated in this prospective, randomized, double-blind trial that lasted 6 months; 347 of these women also participated in a 6-month extension. Women with repeated bleeding or an increase in endometrial thickness to above 5 mm were subjected to saline-infused sonohysterography or hysteroscopy with biopsy. Sonographic, histologic, and clinical findings were adjudicated by a panel of 4 experts blinded with respect to patients’ treatments. All adjudicated patients were grouped into 15 diagnostic categories according to predefined criteria.
RESULTS: Three hundred thirty-four women needed adjudication during the core phase, 73 (14.7%) of those taking raloxifene and 261 (50.9%) taking continuous combined estrogen plus progestin therapy (P < .001). Compared with raloxifene, women using continuous combined estrogen plus progestin therapy had significantly higher rates of benign endometrial proliferation (8.8 versus 1.2%, P < .001), endometrial polyps (4.3 versus 2.0%, P = .048), and cystic atrophy (5.5 versus 1.2%, P < .001).
CONCLUSION: Women using continuous combined estrogen plus progestin therapy more often have benign endometrial pathology and, in our study, more often required the protocol-specific gynecological follow-up assessments for safety reasons, as compared with those using raloxifene. These findings are of clinical relevance when choosing the most appropriate therapy for postmenopausal health risks such as osteoporosis.
LEVEL OF EVIDENCE: I
For several decades, estrogen plus progestin therapy has been considered the criterion standard for the prevention of postmenopausal symptoms and health risks, such as vasomotor and genitourinary complaints, osteoporosis, cardiovascular disease, and even dementia. Although several recently published large, prospective trials1–4 did not confirm the expected reduction of cardiovascular and cerebrovascular events in long-term users and have thus led to a new, more critical risk-benefit evaluation of chronic estrogen plus progestin therapy,5 the general perception of an overall benefit from estrogen plus progestin therapy has, in essence, remained unchanged among gynecologists. One of the arguments commonly used by European advocates of estrogen plus progestin therapy to point out the irrelevance of the recent findings is the fact that all of the above-mentioned trials were performed in the United States, where the combined use of conjugated equine estrogens and medroxyprogesterone acetate is the standard regimen of continuous combined estrogen plus progestin therapy. Although it is often argued that the risk-to-benefit ratio of modern, European-style continuous combined estrogen plus progestin therapy formulations consisting of 17β-estradiol (E2) and norethisterone acetate may be different and more favorable than conjugated equine estrogens and medroxyprogesterone acetate, data from large, prospective clinical end point studies examining these formulations are lacking.
The EURALOX Study was conceived in 1996 and conducted from 1997 until 2000 for the purpose of directly comparing the most widely available European standard continuous combined estrogen plus progestin therapy regimen of 17β-E2 and norethisterone acetate (Kliogest/Kliofem; Novo Nordisk A/S, Bagsværd, Denmark) with the therapeutic alternative of a selective estrogen receptor modulator. Raloxifene, a second-generation selective estrogen receptor modulator that was an investigational drug in 1997 but soon became commercially available in Europe in 1998, is a nonsteroidal benzothiophene derivative.6 The compound possesses estrogen agonist effects in the skeletal system and is efficacious in the prevention7 and treatment of postmenopausal osteoporosis.8,9 In the cardiovascular system, raloxifene reduces total and low-density lipoprotein cholesterol10,11 and lipoprotein(a),12 induces nitric oxide–dependent vascular wall relaxation,13 and slows atherosclerotic plaque formation in most but not all animal models.14–16 In humans, raloxifene recently has been reported to reduce the risk of cardiovascular and cerebrovascular clinical events in the high-risk subset of women from the Multiple Outcomes of Raloxifene Evaluation study cohort.17 In the breast and endometrium, raloxifene has estrogen antagonist effects and is associated with reduced incidence of newly diagnosed breast cancer18,19 and no endometrial proliferation20 and uterine bleeding,21,22 making the addition of a progestin unnecessary. However, raloxifene does not alleviate postmenopausal vasomotor symptoms and has been reported to increase the proportion of women with hot flushes by 7% in early7 and by 3% in the later postmenopause.8 As with estrogen plus progestin therapy, the incidence of venous thromboembolic events is slightly but statistically significantly increased.8
The primary purpose of the EURALOX study was to compare directly the uterine effects of the 2 treatments. The results of the main gynecological outcomes (bleeding pattern, endometrial thickness, uterine volume) have been reported previously,22 as have the results on several of the nongynecological secondary end points.11,23 However, because bleeding patterns and endometrial thickness assessed by ultrasound are not sufficient to establish a gynecological diagnosis, we applied a uterine safety algorithm to all participating women, which allowed us either to assign a gynecological diagnosis or to classify a woman’s endometrium as “normal.” In this report, we will describe the algorithm and the distribution of findings observed after treatment with continuous combined estrogen plus progestin therapy or raloxifene.
MATERIALS AND METHODS
The EURALOX Study was a multicenter, prospective, parallel, randomized, double-blind study comparing uterine effects of a European continuous combined estrogen plus progestin therapy regimen and raloxifene. The trial was conducted between December 1997 and February 2000 in 19 countries with 129 participating gynecological clinics throughout Europe, in Israel, and in South Africa. Women aged 66 years or less who had been in their natural menopause for at least 2 years at the time of study start were eligible to participate if they were willing to receive either treatment and if their postmenopausal risk-benefit profile, as assessed with a standardized questionnaire, suggested a health benefit from the long-term use of both drugs. Subjects were excluded if they had a history of hysterectomy; ovariectomy; breast cancer, estrogen-dependent cancer, or any other cancer within the past 5 years; a history of venous thromboembolic events or liver disease; if they had an endometrial thickness of more than 5 mm or any clinically significant endometrial or ovarian pathology, as determined by transvaginal ultrasound and uterine biopsy; if they had suspicious mammographic findings; or if they had any contraindication for the use of either study drug. Previous treatment with estrogens/progestins required a 6-month washout period.
The study protocol and informed consent form complied with the guidelines of the Declaration of Helsinki and were approved by local ethics review boards. After a screening period of 4 to 7 weeks in duration in which all women received a single-blind placebo lead-in medication, at visit 2 eligible women were randomly assigned to receive either 60 mg of raloxifene (Evista; Eli Lilly, Indianapolis, IN) or a continuous combined estrogen plus progestin therapy preparation containing 2 mg of 17β-E2 and 1 mg of norethisterone acetate (Kliogest/Kliofem) per day. Double-blind study medication was provided to the participating centers in labeled containers, and randomization was performed by assigning numbered medication kits in sequence beginning with the lowest number available. The random allocation sequence of medication kits was created by the sponsor using a computer program and a block size of 4. The core phase of the double-blind treatment period had a duration of 6 months; women in predefined centers from 6 of the 19 participating countries had the option to take part in an extension up to month 12. Patients, investigators, and staff members of the sponsor who were involved in conducting the trial were unblinded only after the database was locked. A more detailed description of the trial design, randomization, and blinding procedures has been published elsewhere.11,22,23
The main research hypothesis of the trial was that treatment with raloxifene, in contrast to continuous combined estrogen plus progestin therapy, would not be associated with any signs of endometrial proliferation. Bleeding/spotting rates and the changes in endometrial thickness and uterine volume were the primary end points of the trial. In a diary throughout the study, patients recorded the frequency of uterine bleeding and spotting. Endometrial thickness and uterine volume were measured by transvaginal ultrasonography at baseline and after 6 months, as well as after 12 months in the extension patients. All transvaginal ultrasonographies were recorded on tape by the investigators according to a standard procedure. The uterus was examined in 3 dimensions, and the endometrial thickness of the long and short axis projection from 1 endometrial/myometrial interface to the opposite interface (double layer) was recorded and measured. All tapes were reassessed by a central reader (P.N.), who was blinded with respect to treatment code. Details regarding the quality control and efficacy analysis of the transvaginal ultrasonographies have been provided elsewhere.22
According to local medical practice and patient willingness, patients who were eligible for further screening did (group A) or did not (group B) undergo a blinded endometrial Pipelle biopsy at baseline and after 6 months, which was also evaluated by a central reader (M.G.) who was blinded to treatment code. Women with any clinically significant endometrial (endometrial thickness more than 5 mm of focal abnormalities) or ovarian pathology at baseline, as determined by central reading of transvaginal ultrasonography or endometrial biopsy, were excluded.
All women presented after 3 months (visit 3) of double-blind treatment. No routine uterine procedures were performed in patients of either group at this time; however, women in group B who had documented repeated vaginal spotting/bleeding in the first 3 months (for definition of “repeated,” see below) were subjected to uterine safety testing in accordance with a protocol-specific gynecologic surveillance algorithm: a transvaginal ultrasonography was preformed as a first step, and if it revealed an endometrial thickness of more than 5 mm, saline-infused sonohysterography or hysteroscopy/biopsy were performed. If the endometrium, as measured by saline-infused sonohysterography, was uniformly thin (single layer less than 3 mm), there was no further testing. In contrast, a Pipelle biopsy had to be taken in case of a uniformly thickened endometrium. If saline-infused sonohysterography revealed asymmetrical thickening of the endometrium, hysteroscopy with guided biopsy was required. In centers where neither saline-infused sonohysterography nor hysteroscopy and biopsy were available, abnormal transvaginal ultrasonography findings prompted a dilation and curettage (D&C; this affected a total of 17 patients). In the case of disagreement on endometrial thickness between the investigator and the central reader, the latter made a binding recommendation on further diagnostic procedures to the investigator to be performed within 1 month.
After 6 months of treatment (visit 4), all women had a transvaginal ultrasonography performed, and in cases of repeated bleeding/spotting or of an endometrial thickness of more than 5 mm, the uterine algorithm was followed as described above. In all group A women not required to follow the uterine surveillance algorithm for safety reasons, a second routine endometrial Pipelle biopsy was taken. For those women who participated in the study extension, the procedures at 12 months (visit 5) were identical to those of visit 4.
Of the primary study outcomes, the change in endometrial thickness was expected to show the most subtle differences and therefore determined the sample size. Details of the sample size calculation and statistical analysis methods have also been described previously, along with the primary outcomes of the study.22
In this report, we describe the methodology and results of the gynecologic adjudication process that was performed for all patients who were either subjected to the uterine surveillance algorithm described above or had any abnormal, unclear, or discrepant findings during the routine uterine assessments. It was the goal of the adjudication process to obtain 1 final, unified, consensus-based diagnosis taking into account all endometrial findings collected with the different diagnostic methods (transvaginal ultrasonography, saline-infused sonohysterography, hysteroscopy, biopsy, bleeding pattern). The adjudication committee consisted of the 2 central readers and 2 other gynecologists who were not investigators in the trial and who were also blinded with respect to the patients’ treatment codes. The committee grouped the descriptive tissue diagnoses from the biopsy readings in 6 categories (Table 1). Next, the committee reviewed and adjudicated all patients who met 1 or several of the following criteria: long-axis transvaginal ultrasonography endometrial thickness more than 5 mm or short-axis transvaginal ultrasonography endometrial thickness more than 6 mm; focal endometrial abnormalities in transvaginal ultrasonography; all patients who underwent saline-infused sonohysterography, hysteroscopy, or D&C, regardless of reason and outcome; all patients with descriptive tissue diagnoses from blinded biopsy, guided biopsy, or curettage classified other than “normal” (Table 1); and all patients with “repeated bleeding/spotting” as predefined in the study instructions; that is, patients who bled at least twice in at least 1 visit interval after randomization and at least once during the third 4-week period of this interval or later. All patients not requiring adjudication according to these criteria were classified as “normal.” For patients with any biopsy result other than atrophic or inactive endometrium (categories 2–5; Table 1), the tissue diagnosis was taken as the patient’s final diagnosis, regardless of the transvaginal ultrasonography findings. In contrast, all patients with a normal biopsy result but with repeated bleeding uniformly increased transvaginal ultrasonography endometrial thickness or focal endometrial abnormalities in transvaginal ultrasonography, saline-infused sonohysterography, or hysteroscopy were adjudicated individually. For final classification, the committee placed each patient into 1 of 15 diagnostic categories (Table 2).
Proportions of patients adjudicated and not adjudicated and with and without normal and nonnormal diagnoses were compared among the treatment groups in each of the core and extension phases of the study using the Fisher exact test. In a post hoc analysis, the power for detecting a statistically significant between-group difference in patient numbers undergoing adjudication was more than 99% for the core phase and 98% for the extension phase.
The numbers of women screened, randomly assigned, withdrawn, and analyzed in the core and extension phases of the study are summarized in Figure 1. There were no major differences in baseline characteristics between treatment groups (Table 3).
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. Cited Here...
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