Received for publication October 19, 2005; revised March 8, 2006; accepted March 8, 2006

Transcription

1 American Journal of Obstetrics and Gynecology (2006) 195, Effects of Tibolone and Continuous Combined Conjugated Equine Estrogen/Medroxyprogesterone Acetate on the Endometrium and Vaginal Bleeding: Results of the OPAL Study Robert D. Langer, MD, MPH, a, * Britt Marie Landgren, MD, b Janice Rymer, MD, c Frans A. Helmond, PhD, d for the OPAL Investigators Gesinger Health System, a Danville, PA; Karolinska Hospital and Institutet, b Stockholm, Sweden; Guy s, King s, and St Thomas School of Medicine, King s College, c London, UK; Organon International, d Roseland, NJ Received for publication October 19, 2005; revised March 8, 2006; accepted March 8, 2006 KEY WORDS Endometrial safety Hormone therapy OPAL Tibolone Vaginal bleeding Objectives: The primary objective of the Osteoporosis Prevention and Arterial effects of tibo- Lone study was to compare the effect of tibolone and placebo on the progression of the common carotid artery intima-medial thickness; the common carotid artery intima-medial thickness and bone data will be presented elsewhere. A secondary objective was to assess the effects of tibolone (2.5 mg), continuous combined conjugated equine estrogen/medroxyprogesterone acetate [0.625/ 2.5 mg], and placebo on the endometrium and vaginal bleeding; these results are the subject of this report. Study design: This 3-year, three-arm, international, randomized, double-blind, parallel group, placebo-controlled clinical trial enrolled 866 postmenopausal women (aged years). The endometrium was assessed by annual transvaginal ultrasound scans and end-of-study biopsies (United States/United Kingdom centers only). Vaginal bleeding was recorded in daily diaries. Results: Endometrial thickness measured by transvaginal ultrasound scan increased slightly during the first year with tibolone and conjugated equine estrogen/medroxyprogesterone acetate, without any further progression. After 3 years, there were no significant differences between the tibolone, conjugated equine estrogen/medroxyprogesterone acetate, and placebo groups in the incidence of proliferation (1.4%, 4.8%, and 0%, respectively), endometrial hyperplasia (0% in all groups), or cancer (1, 0, and 1 case, respectively). During the first 3 months, bleeding/ spotting rates were greater with conjugated equine estrogen/medroxyprogesterone acetate (48%) than with tibolone (18%; P!.001) or placebo (3%; P!.001). During 3 years of treatment, the incidence of bleeding/spotting was 66%, 48%, and 23% for conjugated equine estrogen/medroxyprogesterone acetate, tibolone, and placebo, respectively. The mean number of bleeding/spotting days was greater in the conjugated equine estrogen/medroxyprogesterone acetate than the tibolone Funded by NV Organon, Oss, The Netherlands. * Reprint requests: Robert D. Langer, MD, MPH, Center for Health Research & Rural Advocacy, Geisinger Health System, 100 N Academy Avenue, Danville, PA rdlanger@geisinger.edu /$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi: /j.ajog

2 Langer et al 1321 or placebo groups (61, 28, and 7 days, respectively; P =.023 vs tibolone; P!.0001 vs placebo). The mean number of bleeding/spotting episodes was also greater in the conjugated equine estrogen/medroxyprogesterone acetate group (13 episodes) compared with the tibolone group (six episodes; P!.001) and placebo group (four episodes; P!.001). Vaginal bleeding was more commonly reported as an adverse event with conjugated equine estrogen/medroxyprogesterone acetate than tibolone (26.4% vs 10.8%, P!.0001) and as the reason for premature discontinuation (9% vs 2%, P =.001). Conclusion: Compared with conjugated equine estrogen/medroxyprogesterone acetate, tibolone has a better tolerability profile with respect to vaginal bleeding but with a similar endometrial safety. These results reinforce the endometrial safety profile of tibolone. Ó 2006 Mosby, Inc. All rights reserved. Conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) is one of the most commonly used estrogen-progestogen therapy (EPT) combinations and its endometrial safety has been confirmed in largescale studies. 1-3 However, it has been associated with frequent bleeding and spotting episodes, especially in the first 6 months of treatment. 4 Tibolone is a selective tissue estrogenic activity regulator 5 that is effective in the prevention of osteoporosis and treatment of climacteric symptoms and does not stimulate endometrial and breast tissue. 6 In the endometrium, tibolone locally reduces estrogenic activity via two different routes. Tibolone decreases the activity of the enzyme sulfatase and increases the activity of the enzyme sulfotransferase. These two enzymes are involved in the activation and deactivation, respectively, of estrogenic compounds, resulting in a shift toward deactivation. The other route is the metabolization of the two estrogenic hydroxymetabolites of tibolone back into tibolone, which can be further metabolized locally into the D 4 -isomer, which has progestogenic but no estrogenic properties. 7-9 Tibolone is associated with a low incidence of endometrial hyperplasia and vaginal bleeding and does not require the addition of a progestogen The Osteoporosis Prevention and Arterial effects of tibolone (OPAL) 17 study was conducted to determine the effects of tibolone, continuous combined CEE/ MPA, and placebo on bone mineral density and carotid intima-media thickness (CIMT) in postmenopausal women. This double-blind placebo-controlled trial also captured unique long-term (3 years) comparative data on endometrial safety and vaginal bleeding for tibolone and. Methods This three-arm, multicenter, randomized, double-blind, placebo-controlled study was conducted in six centers in the United States (US) and five centers in Europe. Healthy postmenopausal women (aged years and with a body mass index of O19 and %32 kg/m 2 ) who had been amenorrheic for R1 year were enrolled. If the date of final menstruation was unclear, the woman was to have used hormone therapy (HT) for O2 years and be O53 years old or fulfill the US Food and Drug Administration (FDA) criteria for menopause (serum estradiol %20 pg/ml [or 73 pmol/l] and follicle-stimulating hormone R40 miu/ml). Per study protocol, an intact uterus was required for enrollment in the US centers, whereas in European centers, women with or without a uterus were eligible. A washout period of 8 weeks was required for oral estrogens with or without progestogens, androgens, or selective estrogen receptor modulators (SERMs), 4 weeks for transdermal or local sex steroids, and 20 weeks for injections of MPAcontaining contraceptives. Women were excluded if they had an abnormal cervical Pap smear result, double-layer endometrial thickness of O5 mm as measured by transvaginal ultrasound scan (TVUS), endometrial hyperplasia, unexplained vaginal bleeding that required follow-up, uncontrolled hypertension, current or recent alcohol and/or drug abuse, Type I diabetes mellitus, low total fasting cholesterol, recent history of myocardial infarction, heart failure requiring pharmacologic treatment, current or previous stroke, thrombophlebitis, thromboembolic disorder, gallbladder disease or malignancy (except nonmelanoma skin cancer), suspected breast malignancy, relevant abnormal electrocardiogram (ECG) or laboratory values, serious decompensated renal or liver disease, a carotid ultrasound alert, carotid arteries that were difficult to image using the study protocol, any condition that could alter the pharmacokinetics of the investigational drugs, or hypersensitivity to tibolone or. Current or recent prolonged use of systemic corticosteroids or hepatic microsomal enzymeinducing anticonvulsant medication (or other drugs known to alter the pharmacokinetics of steroids), investigational drug use within the last 60 days, a requirement for medication to treat or prevent dyslipidemia and/or osteoporosis, or a requirement for sex steroids, androgens, or SERMs were also reasons for exclusion. All women provided written informed consent according to the regulations at each participating institution. The study was conducted according to Good Clinical Practice, in full compliance with the Declaration of Helsinki including revisions, and the protocol was

3 1322 Langer et al Table I Baseline characteristics Tibolone (n = 286) (n = 284) (n = 287) Mean (G SD) age (years) 58.9 G G G 6.6 Mean (G SD) BMI (kg/m 2 ) 25.2 G G G 2.9 Mean (G SD) weight (kg) 67.3 G G G 9.1 Mean (G SD) height (cm) G G G 5.9 Race Caucasian 275 (96.1%) 275 (96.8%) 274 (95.4%) Asian 4 (1.3%) 5 (1.7%) 7 (2.4%) Other 7 (2.4%) 4 (1.4%) 6 (2.0%) Mean (G SD) time since 10.8 G G G 7.8 menopause (years) Intact uterus 228 (79.7%) 236 (83.0%) 243 (84.6%) Previous HT use 133 (46.5%) 142 (50.0%) 131 (45.6%) BMI, Body mass index. Table II Endometrial thickness (mm) assessed by TVUS at baseline and annually during treatment with tibolone,, or placebo (mean G SD) Tibolone Baseline 2.3 G 1.1 (n = 216) 2.4 G 1.1 (n = 219) 2.4 G 1.1 (n = 230) Week G 2.6 (n = 187) 3.1 G 1.8 (n = 197) 2.4 G 1.3 (n = 200) Week G 2.3 (n = 167) 3.2 G 1.6 (n = 177) 2.6 G 1.2 (n = 178) Week G 2.0 (n = 152) 3.0 G 1.3 (n = 164) 2.6 G 1.1 (n = 172) End point 3.6 G 2.0 (n = 191) 3.2 G 1.7 (n = 200) 2.6 G 1.3 (n = 211) approved by the institutional review boards of the participating clinics. Medication The women were randomized in a 1:1:1 ratio to receive oral tibolone 2.5 mg, continuous combined 0.625/2.5 mg, or placebo for 3 years (39 cycles of 28 days). The investigational products were blinded using a doubledummy technique. All subjects also received oral calcium supplements (500 mg/day). Concomitant medication (other than that specifically prohibited by the protocol) was permitted at the discretion of the investigator. Assessments Screening evaluations included a medical and gynecologic history, physical and gynecologic examination (including pelvic examination, cervical Pap smear, and TVUS), vital signs, ECG, mammography, pretreatment signs and symptoms and concurrent medications, a carotid ultrasound, dual energy x-ray absorptiometry measurements of bone mineral density, blood lipid levels, routine chemistry, hematology, and urinalysis. Eligible subjects were assigned code numbers in the order of their randomization into the study. Smoking and alcohol consumption and any symptoms and concomitant medications were recorded. The subjects also completed a quality-of-life questionnaire. Follow-up visits were performed at 3 months after randomization and every 6 months thereafter. At all centers, the endometrium was assessed by TVUS after 52, 104, and 156 weeks of treatment (or at the final visit if withdrawn prematurely). At baseline and throughout most of the study, a double-wall endometrial thickness of %5 mm was interpreted as supporting a diagnosis of no endometrial cancer. At the end of the study, to be more conservative, this was changed to %4 mm. Any relevant comments pertaining to the scan were recorded and an appropriate follow-up was conducted in the case of clinically significant findings. In the US/United Kingdom (UK) centers only (7 of 11 centers with 46.9% of women enrolled), an endometrial biopsy was performed at screening and the end of the study using Pipelle endometrial sampler or an alternative acceptable method. Additional biopsies were performed during the study as clinically indicated (eg, undiagnosed abnormal vaginal bleeding, endometrial double-wall thickness of O5 mm). Subjects with endometrial hyperplasia or cancer were not eligible to be enrolled in the study. All biopsy specimens were shipped in a vial containing 10% buffered formalin to a central cytology/pathology laboratory for processing and analysis. Biopsies were evaluated in accordance with the FDA 18 and European Agency for the Evaluation of Medicinal Products 19 guidelines. The results of the histologic examination were classified as follows 20 :

4 Langer et al 1323 Table III Summary of the endometrial biopsy findings at baseline and end point during 3 years of treatment with tibolone,, or placebo Number of women with Tibolone P value* Baseline biopsies Evaluable 86 (75.4%) 92 (77.3%) 89 (75.4%) Nonevaluable 28 (24.6%) 27 (22.7%) 29 (24.6%) 3-year biopsies Evaluable 47 (77.0%) 52 (71.2%) 41 (60.3%) Nonevaluable 14 (23.0%) 21 (28.8%) 27 (39.7%) End point biopsies Evaluable 57 (80.3%) 65 (75.6%) 49 (63.6%) Nonevaluable 14 (19.7%) 21 (24.4%) 28 (36.3%) Proliferation at baseline 0 (0.0%) 5 (4.8%) 1 (0.8%) y.2128 z.0661 x Proliferation at end point 1 (1.4%) 7 (8.1%) 0 (0.0%).4797 y.0146 z.0733 x Hyperplasia at end point NA Endometrial cancer k y at end point * P-values based on Fisher s exact test. y Tibolone vs placebo. z vs placebo. x Tibolone vs. k Non-US/UK subject: no endometrial biopsy performed (cancer diagnosis following surgery) z.4522 x Table IV Incidence of vaginal bleeding/spotting during treatment with tibolone,, or placebo (n; %) P value* Tibolone (n = 222) (n = 232) (n = 235) Tibolone vs Tibolone vs vs Bleeding/Spotting 107 (48.2%) 153 (65.9%) 53 (22.6%)!0.001!0.001!0.001 Spotting only 59 (26.6%) 76 (32.8%) 42 (17.9%) !0.01 Bleeding only 48 (21.6%) 77 (33.2%) 11 (4.7%) 0.007!0.001!0.001 CMH, Cochran-Mantel Haenzel. * P value based on CMH test adjusted for centers. 0: No tissue obtained 1: Tissue insufficient for diagnosis 2: Atrophic 3: Inactive 4: Proliferative 5: Secretory 6: Menstrual type 7: Simple hyperplasia 8: Complex hyperplasia 9: Atypical hyperplasia 10: Carcinoma (type to be specified) Biopsies were considered normal if they were classified as atrophic or inactive. If there was no or insufficient tissue available for diagnosis but the TVUS was %4 mm, the biopsy was also considered normal. Any subjects who were found to have endometrial hyperplasia during the study were managed by their physicians according to the current local standard of care. In the event that progestogen therapy was prescribed, the subject stopped investigational treatment in order to avoid inappropriate concomitant use of two progestational drugs. All other subjects continued in the study. For all nonhysterectomized study participants, vaginal bleeding was recorded in daily diaries and collected at each clinic visit (baseline and weeks 12, 28, 52, 76, 104, 128, and 156). The following definitions were used for diary recordings: Bleeding: any vaginal flow requiring more than one sanitary napkin or tampon per day

5 1324 Langer et al Endometrium The mean endometrial double-wall thickness (as assessed by TVUS) was similar in all three groups at baseline ( mm). During the first year of treatment, there was a small increase in endometrial thickness in the tibolone and the groups. After 2 and 3 years of treatment, the thickness was very similar to that observed after the first year of treatment and no further progression was observed (Table II). Biopsy results Figure Percentage of women with vaginal bleeding/spotting episodes by 12-week intervals (three treatment cycles). Spotting: any vaginal flow requiring not more than one sanitary napkin or tampon per day Details of all other assessments are provided elsewhere. 17 Statistical analyses Tabulations and summary statistics were performed for TVUS and endometrial biopsy findings. For the endometrial biopsies, the number of subjects was tabulated in terms of the histologic categories of normal (atrophic, inactive, proliferative, secretory, or menstrual), hyperplasia (simple, complex, or atypical), or cancer. In cases where the endometrial biopsy material was insufficient for diagnosis, the TVUS finding of an endometrium %4 mm resulted in inclusion in the normal category. The proportion of women reporting any bleeding or spotting was compared between the tibolone and placebo groups and between the and placebo groups using the Cochran-Mantel-Haenszel test adjusted for centers. An episode was defined as one or more consecutive days during which bleeding or spotting was recorded in the diary bounded by bleeding/ spotting-free days. Results A total of 866 women were randomized, of whom 857 received at least one dose of study medication (286 in the tibolone group, 284 in the group, and 287 in the placebo group). There were no statistically significant differences between the groups with regard to baseline characteristics (Table I). The percentage of women who completed the study was similar in each group (69% tibolone, 72%, and 70% placebo). A summary of biopsy findings is shown in Table III. The number of subjects with baseline biopsies was 351 (114 tibolone, 119, and 118 placebo). The number of end point biopsies was 234 (71, 86, and 77, respectively). The percentage of subjects with evaluable baseline or end point biopsies was similar among groups, with the possible exception of the lower percentage of evaluable end point biopsies in the placebo group. No women developed hyperplasia. Two women were diagnosed with endometrial cancer during the study. One case was a participant in the placebo group who did not have a biopsy performed (non-us/uk subject) but who was diagnosed following surgery after approximately 6 months in the study. The other case was a participant in the tibolone group who was diagnosed by endometrial biopsy 3 months after the end of the 3-year study. In that case, TVUS revealed endometrial thickness of 3 mm at baseline and 8 mm at month 39. Baseline and last visit endometrial specimens were unobtainable due to tissue being insufficient for diagnosis, but a subsequent attempt, after the study was complete, yielded adequate tissue. Vaginal bleeding The group had a higher incidence (66%, P!.001 vs both tibolone and placebo) of bleeding/ spotting episodes than either the tibolone group (48%) or the placebo group (23%) (Table IV). The higher incidence of bleeding/spotting in the group was particularly notable in the first 12 weeks, when 47.8% of women reported bleeding/spotting compared with 17.6% (P!.001) in the tibolone group and 3.4% (P!.001) in the placebo group (Figure, first 12 week interval). After 3 years of treatment, the incidence of bleeding/spotting episodes was reported in 22.3% of women given (P! vs both tibolone and placebo), 7.5% of those given tibolone and 2.8% given placebo (Figure, last 12 week interval). As shown in Table V, the mean number of bleeding/spotting days and bleeding/spotting episodes was also greater in the group than in the tibolone and placebo groups (bleeding/spotting days: 61, 28 and 7, respectively, P =.023 vs tibolone and P!.0001 vs placebo;

6 Langer et al 1325 Table V Summary of bleeding/spotting parameters in women reporting bleeding/spotting during treatment with tibolone,, or placebo (All-Subjects-Treated Group) P value* Tibolone (n = 107) (n = 153) (n = 53) Tibolone vs Tibolone vs vs Number of bleeding/spotting days Mean G SD 28.0 G G G !0.0001!.0001 Median Range Number of bleeding/spotting episodes Mean G SD 5.8 G G G 7.2! !.0001 Median Range Duration of bleeding/spotting episodes (days) Mean G SD 4.7 G G G !0.0001!.0001 Median Range * P values based on Wilcoxon test. bleeding/spotting episodes: 13, 6, and 4, respectively, P!.001 vs tibolone and P!.0001 vs placebo). The mean duration of bleeding/spotting episodes was similar in the and tibolone groups and longer than in the placebo group (Table V). Vaginal bleeding was reported as an adverse event by more women in the group (n = 75; 26.4%, P!.0001 vs both tibolone and placebo) than in the tibolone (n = 31; 10.8%) and placebo (n = 9; 3.1%) groups. The percentage of women who discontinued the study due to vaginal bleeding was 9% (n = 25, P =.001 vs tibolone) in the group compared with 2% (n = 7) in the tibolone group and!1% (n = 1) in the placebo group. Most of these discontinuations occurred during the first 3 months of treatment (14/23 [61%]), although some occurred as late as the second or third year (4/23 [17%]). Comment The TVUS and biopsy findings of the OPAL study confirm and extend previous clinical trial results with respect to the endometrial safety of tibolone and its favorable vaginal bleeding profile when compared with continuous combined preparations. 13,15 The incidence of endometrial proliferation in the OPAL study was low in all three treatment groups and none of the women in any of the treatment groups developed endometrial hyperplasia during the 3-year study. Two cases of endometrial cancer were found, one in the placebo group and one in the tibolone group. The biopsy results should be interpreted with caution because only about half of the total study population had biopsies performed, as was prespecified in the protocol. Previous clinical trials have also reported a preponderance of atrophic endometrial histology in postmenopausal women treated with tibolone, and no increased risk of hyperplasia or cancer ,16 For example, in a 2-year, open-label study conducted in 150 women, the endometrium remained atrophic in 92% of subjects taking tibolone, whereas 6.5% showed a change to a weakly proliferative pattern; the endometrial pattern was classified as simple hyperplasia in one woman. 10 Similar results were seen in a study of 168 women treated with tibolone for between 1.5 months and 6 years, with 90% showing no histologic change and the remainder having only mild proliferative changes. 11 In a 5-year observational study with standard and low-dose EPT, tibolone, and raloxifene mean endometrial thickness was not significantly affected by any of the treatment regimens studied. 21 A 2-year prevention of osteoporosis dose-finding study of postmenopausal women demonstrated that the incidence of hyperplasia was similar in tibolonetreated subjects with a uterus (3 of 600) compared with placebo-treated subjects (1 of 146). Three cases of endometrial cancer were observed in that study, but in each case, preexisting carcinoma was later detected when the initial biopsy samples were more extensively examined. 16 The present clinical trial results do not support recent findings in two UK observational studies. A casecontrol study showed an increased risk of endometrial cancer when compared with users of sequential HT (RR = 1.58; 95% CI: ). However, the authors did not present any data on tibolone-only users and reported that their data were fragile and biased and uncontrolled confounding could not be excluded. 22

7 1326 Langer et al The UK Million Women Study (MWS) recently reported follow-up data on 716,738 postmenopausal women 23 who used daily combined estrogen-progestin (22%), sequential estrogen-progestin (45%), estrogen only (4%), and tibolone (9%). During the follow-up period of an average 3.4 years, there were 1320 cases of invasive endometrial cancer. The risk of endometrial cancer was reduced with the use of continuous combined estrogen-progestin (RR = 0.71; 95% CI: ) and increased with estrogen-only (RR = 1.45; 95% CI: ) and tibolone (RR = 1.79; 95% CI: ). In the 5.6-year Women s Health Initiative (WHI) trial of estrogen plus progestin versus placebo, the risk of endometrial cancer was also reduced with estrogen-progestin preparations (RR = 0.81; 95% CI: ). 24 The WHI trial did not include tibolone as one of the comparators. It has been suggested that the tibolone results in observational trials may reflect preferential prescribing. Data from the UK MediPlus Primary Care database indicate that clinicians often prescribed tibolone for women at increased risks for breast and endometrial cancer. 25 Women who were prescribed tibolone in the UK had chronic breast disease, a personal history of breast cancer, previous dysfunctional uterine bleeding, hypertension, and previous uterine operations more often than users of other forms of postmenopausal HT. Most importantly, more women who were prescribed tibolone had a history of (long-term) treatment with unopposed estrogen. These data argue that preferential prescribing of tibolone for women at higher risk of endometrial cancer could explain the apparent increased risk reported in the UK MWS cohort. It is important to qualify the MWS as an observational study. Evidence from clinical trials of tibolone, including the present study, do not support an increase in hyperplasia, which is believed to be a precursor to endometrial carcinoma, nor do they provide support for an excess of carcinoma itself. Double-layer endometrial thickness measured by TVUS in the OPAL study showed a similar increase during the first year of treatment in both the tibolone and the groups. No increase was seen thereafter in either group. The degree of increase was small, with the mean thickness for both groups remaining!4 mm. A previous double-blind, randomized comparison of tibolone with continuous combined 17b-estradiol (2 mg) plus norethisterone acetate (NETA; 1 mg) in 100 postmenopausal women also revealed no differences in endometrial thickness between the groups at any assessment during the 1-year study. 15 However, both oral and transdermal 17b-estradiol sequentially combined with dydrogesterone caused a significant increase in endometrial thickness after 2 years in a randomized study involving 85 women, whereas there were no differences between tibolone and a control group. 26 The long-term effects of tibolone on the endometrium have been compared with those in an age-matched control group in an open-label study that recruited 110 recently postmenopausal women. 27 After 10 years, 57 subjects remained in the study and there was no significant difference between the mean endometrial thickness in the tibolone group (2.2 mm), as compared with the untreated control group (1.8 mm; P =.33). Although the OPAL study revealed no differences between tibolone and continuous combined with respect to endometrial safety, the incidence of vaginal bleeding/spotting episodes, as well as the mean number of bleeding/spotting days and bleeding/spotting episodes, was clearly higher with. This effect was particularly noticeable during the first 3 months of treatment, a period during which women often decide whether or not to continue with HT. In addition, more women given reported vaginal bleeding as an adverse event (26.4% vs 10.8%) and stated it as the reason for premature discontinuation (9% vs 2%). This bleeding profile is consistent with the results from previous studies comparing tibolone with other HT regimens, including continuous combined. In a 1-year, double-blind study involving 501 postmenopausal women, the vaginal bleeding rate was significantly (P!.01) lower with tibolone than with CEE/ MPA during weeks 1 to 12 (23% vs 41%) and weeks 13 to 24 (15% vs 27%). 13 Similar findings were seen in another smaller (n = 68), 1-year, double-blind study, in which significantly fewer women had at least 1 day of bleeding/spotting with tibolone than with CEE/ MPA (6% vs 33%; P!.05). 28 Among comparisons with other HT regimens, two large double-blind studies have shown that tibolone results in a significantly (P!.01) lower incidence of bleeding/spotting episodes than continuous combined 17b-estradiol plus NETA, as well as fewer subject discontinuations due to vaginal bleeding. 13,15 In conclusion, the OPAL study confirmed that tibolone has a favorable bleeding profile compared with, while offering similar endometrial safety. References 1. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. 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