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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2207
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 3 911-918
Copyright © 2007 by The Endocrine Society

Endometrial Effects of Tibolone

David F. Archer, Susan Hendrix, J. Chris Gallagher, Janice Rymer, Sven Skouby, Alex Ferenczy, Wil den Hollander, Victoria Stathopoulos, Frans A. Helmond for the Tibolone Histology of the Endometrium and Breast Endpoints (THEBES) Study Group1

Department of Obstetrics and Gynecology (D.F.A.), Contraceptive Research and Development (CONRAD) Clinical Research Center, Eastern Virginia Medical School, Norfolk, Virginia 23507; Wayne State University/Hutzel Women’s Hospital (S.H.), Detroit, Michigan 48201; Bone Metabolism Section (J.C.G.), Creighton University Medical Center, Omaha, Nebraska 68131; Division of Obstetrics and Gynaecology (J.R.), King’s College School of Medicine at Guy’s and St. Thomas’ Hospitals, London SE5 9RT, United Kingdom; Department of Obstetrics and Gynecology (S.S.), Frederiksberg University Hospital, 2000 Copenhagen, Denmark; McGill and Sir Mortimer B. Davis Jewish General Hospital (A.F.), Montréal, Québec, Canada H3T IE2; NV Organon (W.d.H.), 5340 BH Oss, The Netherlands; and Organon International (V.S., F.A.H.), Roseland, New Jersey 07068

Address all correspondence and requests for reprints to: David F. Archer, M.D., Director, CONRAD Clinical Research Center, 601 Colley Avenue, Norfolk, Virginia 23507. E-mail: archerdf{at}evms.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background and Objectives: The Tibolone Histology of the Endometrium and Breast Endpoints Study is a multicenter, randomized, double-blind study designed to address the conflicting reports in the literature about the endometrial safety of tibolone (1.25 or 2.5 mg/d). Tibolone was compared with continuous combined conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) (0.625 + 2.5 mg/d).

Methods: Subjects were randomized in a 1:1:2 ratio to tibolone 1.25 mg/d, 2.5 mg/d, and CEE/MPA, respectively. The one-sided 95% confidence interval (CI) has been evaluated for the incidence of abnormal endometrial histology (hyperplasia or carcinoma) and hyperplasia and carcinoma separately for each of the two treatment groups and the treatment groups combined after 1 and 2 yr of treatment with tibolone, compared with CEE/MPA.

Results: A total of 3240 women were randomized, with 3224 receiving at least one dose of study medication. The incidence and upper one-sided 95% CI for the incidence of abnormal endometrium (hyperplasia or carcinoma), and hyperplasia and carcinoma separately, were calculated at end point, yr 1, and yr 2. The incidence (upper one-sided 95% CI) of abnormal endometrium at end point was 0.0 (0.5), 0.0 (0.4), and 0.2 (0.5) in the tibolone 1.25 mg, 2.5 mg, and CEE/MPA groups, respectively. During the entire treatment period, amenorrhea was reported more frequently with tibolone 1.25 mg (78.7%) and 2.5 mg (71.4%) than CEE/MPA (44.9%).

Conclusion: The Tibolone Histology of the Endometrium and Breast Endpoints Study results confirm previous findings that tibolone does not induce endometrial hyperplasia or carcinoma in postmenopausal women, and it is associated with a better vaginal bleeding profile than CEE/MPA.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TIBOLONE IS USED for the management of climacteric symptoms in postmenopausal women (1, 2). It has beneficial effects on mood and sexual well-being, vaginal atrophy, urogenital symptoms and bone loss, and a low incidence of vaginal bleeding and breast pain (1, 2). The conventional dose of tibolone for treatment of climacteric symptoms is 2.5 mg/d (3, 4, 5). Tibolone is reported to regulate estrogenic activity in a tissue-selective manner, thereby having estrogenic effects on brain, vagina, and bone but not breast or endometrium (6).

Tibolone in the endometrium is irreversibly converted to its {Delta}-4 isomer that binds to both progesterone and androgen receptors (7, 8, 9). Tibolone and its {Delta}-4 isomer induce estrogen-inactivating enzymes 17ß-hydroxysteroid dehydrogenase and sulfotransferase, inhibit sulfatase and enhance locally the deactivation of biologically active estrogenic metabolites (10, 11). Recent in vitro studies show that 3{alpha}- and 3ß-hydroxytibolone metabolites act as progestogens in cultured human endometrial stromal cells, probably due to intracellular conversion of these metabolites to tibolone and the {Delta}-4 isomer (8). These tissue-selective effects in the endometrium explain why tibolone does not stimulate the endometrium and why no adjunctive progestogen is required. The endometrial safety of tibolone has been demonstrated in cynomolgus monkeys (12) and in numerous clinical studies showing a high incidence of atrophic endometrium, no hyperplasia, and no increase in endometrial thickness, compared with women receiving estrogen-progestogen therapy (EPT) (13, 14, 15, 16, 17, 18, 19, 20).

The primary objective of the Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES) was to confirm the endometrial safety of oral tibolone (1.25 and 2.5 mg/d), and a secondary objective was to compare it with continuous combined oral conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) (0.625/2.5 mg/d). Other secondary outcomes compared the vaginal bleeding profile and incidence of breast pain with tibolone to CEE/MPA.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Healthy postmenopausal women (aged 45–65 yr; body mass index ≥ 18 and ≤ 32 kg/m2) with an intact uterus were enrolled in this randomized, active-controlled, double-blind, parallel-group trial. Subjects were recruited from a total of 146 centers (73 recruiting centers in the United States, 69 in Europe, and four in Chile). Subjects had to be amenorrheic for at least 1 yr or amenorrheic for at least 6 months with serum estradiol levels of 20 or less pg/ml and FSH levels of 40 IU/liter or greater and postmenopausal for less than 15 yr. Subjects were included only if their screening biopsy was classified as atrophic or inactive endometrium and they had double-layer endometrial thickness of 6 mm or less as assessed by transvaginal ultrasonography (TVUS). More details on inclusion/exclusion criteria and study design are provided elsewhere (21). Approval was obtained from the independent ethics committee or institutional review board at each participating center, and the trial was conducted in compliance with the Declaration of Helsinki, International Conference on Harmonization Guidelines and Good Clinical Practice. Voluntary written informed consent was obtained from all subjects.

Treatment

Subjects were randomized to oral tibolone 1.25 mg/d, tibolone 2.5 mg/d, or continuous combined CEE 0.625 mg/d, plus MPA 2.5 mg/d, in a 1:1:2 ratio. Study medication was blinded using a double-dummy method. Treatment duration was 2 yr.

Assessments

Endometrial biopsies were obtained, and double-layer endometrial thickness was measured by TVUS at screening and after 1 and 2 yr of treatment or at premature discontinuation. TVUS was performed before endometrial biopsy. Biopsies were performed using a Pipelle suction curette and the tissue was processed at a central laboratory. The resulting tissue block was cut at two levels, with two serial section slides from each level. Two independent gynecological pathologists, blinded to treatment and each other’s diagnosis, examined one slide of each level and classified the results as follows: 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; and 10, carcinoma (22). Results were classified as normal (no hyperplasia/carcinoma, codes 0–6), hyperplasia, or carcinoma. Diagnosis for endometrial polyps was based on surrounding endometrial tissue, unless the polyp was graded as cancerous, in which case the diagnosis was carcinoma. Discrepancies in endometrial polyp histology between the two primary pathologists were not adjudicated by a third pathologist. For polyps, the worst-case diagnosis was taken as the final one.

At screening, no adjudication of histology took place and any reading with code 4 or higher led to exclusion from the study, as did endometrial polyps, metaplasia and/or any abnormal stromal or exoendocervical tissue [endocervical polyp(s), cervical squamous metaplasia, and epithelial atypia of repair were considered normal]. For postbaseline endometrial biopsies, discrepancies in readings of normal tissue (codes 0–6) were not arbitrated, and the higher level code was used as final diagnosis. A third independent, blinded pathologist reviewed the slides in cases of a disagreement between normal and abnormal or between categories for hyperplasia and carcinoma. Agreement between two of three pathologists was used as the final diagnosis. The worst finding was the final diagnosis if there was lack of agreement among pathologists. Classification of the biopsy as category 0 or 1 used TVUS double-wall endometrial thickness to support the diagnosis. A TVUS of 4 mm or less was interpreted as supportive of normal endometrium, whereas greater than 4 mm led to repeating the TVUS and biopsy. A more detailed description of endometrial assessments is provided elsewhere (21).

The vaginal bleeding pattern was assessed at baseline and every 3 months using a bleeding episode log. Subjects recorded days on which bleeding and/or spotting occurred and number of sanitary pads/tampons used. Spotting was defined as any bloody vaginal discharge that required no more than one sanitary pad/tampon per day, and bleeding was defined as any bloody vaginal discharge that required two or more sanitary pads/tampons per day. Vaginal bleeding was reported as an adverse event (AE) if it required further investigation or was considered bothersome by the subject or investigator.

Statistical analyses

The primary parameter was the upper one-sided 95% confidence interval (CI) for incidence of abnormal endometrium (hyperplasia and carcinoma), and hyperplasia and carcinoma separately, for each of the tibolone groups (and the tibolone groups combined) after 1 and 2 yr. Analyses were based on an intention-to-treat (ITT) approach (i.e. all randomized subjects who received at least 90 d of study medication and who had a postbaseline biopsy that could be classified as normal or abnormal). Subjects who had an abnormal postbaseline evaluation before 90 d of study drug treatment were also included in the analyses. Additional analyses were to compare each of the tibolone groups with the CEE/MPA group.

The incidence and upper one-sided 95% CI for the incidence of abnormal endometrium, and hyperplasia and carcinoma separately, were calculated at end point, yr 1 and yr 2. Definitions of incidences of each outcome are as follows: incidence of end point, number of subjects with abnormal endometrium/number of subjects with a postbaseline histological evaluation; incidence of yr 1, number of subjects with abnormal endometrium at or before yr 1 visit/number of subjects with a histological evaluation at yr 1 visit plus number of subjects with abnormal endometrium before yr 1 visit; and incidence of yr 2, number of subjects with abnormal endometrium at or before yr 2 visit/number of subjects with a histological evaluation at yr 2 visit plus number of subjects with abnormal endometrium before yr 2 visit. Histological evaluations of tissue from endometrial polyps or nonendometrial tissue (without surrounding endometrial tissue) were excluded from the primary analyses, except if an endometrial polyp evaluation resulted in a carcinomatous polyp. The upper limit of the 95% CI was based on binomial distribution and calculated with exact methods using SAS MACRO CIBINOM (23). Because this calculates two-sided CIs, the two-sided 90% upper confidence limit was taken as the one-sided 95% CI.

The incidence rate of abnormal endometrium was a secondary parameter. It was defined as the number of abnormal histological evaluations per 100 women years and was calculated as: number of abnormal histological evaluations x 100/(sum of duration of exposure/365.25).

A first analysis of the incidence rate included all abnormal evaluations during the in-treatment period and a second included all postbaseline abnormal evaluations. The incidence rate estimate and a two-sided upper 95% CI for each group were calculated. The calculation of the 95% CI was based on the Pearl Index model (24). Exact 1-{alpha} CI for a Poisson intensity were calculated using an in-house-developed macro (SAS Institute, Cary, NC).

Vaginal bleeding and endometrial thickness were assessed in the all-subjects-treated (AST) group (i.e. all randomized subjects who received at least one dose of study medication). The percentage of subjects with vaginal bleeding or breast pain recorded as an AE or who discontinued the study due to vaginal bleeding or breast pain was compared among the three treatment groups using a two-sided Fisher’s exact test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
A total of 5185 women were screened in 146 recruiting centers of which 3240 were randomized into the study; of these, 3224 received at least one dose of study medication and were included in the AST group (792 tibolone 1.25 mg, 806 tibolone 2.5 mg, and 1626 CEE/MPA). Baseline demographic characteristics were similar among the three groups (Table 1Go). A flow chart of disposition of subjects is shown in Fig. 1Go. ITT analyses involved 641 subjects in tibolone 1.25 mg, 676 in tibolone 2.5 mg, and 1327 in CEE/MPA. A total of 16 subjects from the ITT population were not included in endometrial histology analyses because they were exposed to study drug for less than 90 d and did not have an abnormal biopsy during that time. Percentage of subjects who discontinued the study prematurely was similar in all three groups (42.8, 41.4, and 41.0% in the tibolone 1.25 mg, tibolone 2.5 mg, and CEE/MPA groups, respectively). The main reason for discontinuation was AEs (11.7, 12.5, and 15.1% in the tibolone 1.25 mg, tibolone 2.5 mg, and CEE/MPA groups, respectively), followed by protocol violations and withdrawal of consent.


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  		TABLE 1. Baseline demographic characteristics (AST population)

 

Figure 1
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  		FIG. 1. Disposition of subjects.

 
Endometrial safety

There were no cases of endometrial hyperplasia or carcinoma in either tibolone group during the study. There were two cases of endometrial hyperplasia in the CEE/MPA group: atypical hyperplasia in one case was detected at yr 1 visit and confirmed after hysteroscopy and curettage; Complex hyperplasia in the other case was found at yr 2 visit and the subject completed the study. A subsequent biopsy 3 months later showed atrophic endometrium. There were no cases of carcinoma, although low-grade endometrial stromal sarcoma was diagnosed in one subject in the CEE/MPA group at yr 1 visit.

The one-sided upper 95% CIs for the incidence of abnormal endometrium at end point, yr 1, and yr 2 are shown in Table 2Go. A further four subjects had endometrial abnormalities that were reported as serious AEs by the principal investigator. For one subject in the CEE/MPA group, endometrial hyperplasia was reported as a serious AE based on one biopsy slide reading of complex hyperplasia, although the final diagnosis was secretory mixed type, i.e. normal endometrium. Uterine polyps were reported as serious AEs in three subjects, one in each group.


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  		TABLE 2. The upper one-sided 95% CI for the incidence of abnormal endometrium at end point, yr 1, and yr 2 (ITT population)

 
Proliferative, secretory progestational and menstrual type biopsy results were more common in the CEE/MPA group than the tibolone groups at all time points. Table 3Go summarizes endometrial biopsy findings at end point.


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  		TABLE 3. Endometrial biopsy findings at end point (ITT population)

 
The number of endometrial polyps detected during the study was similar in all three groups. Based on the AST population, histologically confirmed polyps were found in 33 subjects (2.6%) in the combined tibolone group and 40 (3.10%) in the CEE/MPA group during the first year. The corresponding numbers during the second year were 24 (2.5%) and 25 (2.5%). There were no carcinomatous polyps. There were hyperplastic polyps which were scored differently between the two pathologists. Pathologist 1 had one hyperplastic polyp (in the tibolone group), but pathologist 2 scored nine hyperplastic polyps of which eight were in the tibolone group and one in the CEE/MPA group. Double-wall endometrial thickness in the AST population measured by TVUS was 3.1 mm for the combined tibolone group and 3.0 mm for the CEE/MPA group at baseline and 3.6 and 3.4 mm after 2 yr treatment, respectively (Table 4Go).


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  		TABLE 4. Double-wall endometrial thickness in millimeters (mean ± SD) as measured by TVUS by treatment group (AST group)

 
Vaginal bleeding pattern

Vaginal bleeding/spotting was less common with tibolone than with CEE/MPA throughout the treatment period. The percentage of subjects who experienced at least one occurrence of vaginal bleeding/spotting, as assessed at each 3 monthly visit, is shown in Fig. 2Go. During the first 6 months of the treatment period, bleeding occurred in 9.4, 14.5, 12.0, and 36.7% of subjects in the tibolone 1.25 mg, tibolone 2.5 mg, combined tibolone, and CEE/MPA groups, respectively. During the entire 2-yr treatment period, bleeding occurred in 13.3, 20.2, 16.8, and 42.6% of subjects in the tibolone 1.25 mg, tibolone 2.5 mg, combined tibolone, and CEE/MPA groups, respectively; the corresponding percentage of subjects with spotting only was 8.0, 8.4, 8.2, and 12.5%, respectively. Amenorrhea was reported by 78.7% of subjects given tibolone 1.25 mg, 71.4% given tibolone 2.5 mg, and 75.0% for combined tibolone, compared with only 44.9% of those given CEE/MPA. The percentage of subjects with bleeding/spotting decreased during the study in all three groups. Amenorrhea rates during the treatment period of 2 yr are presented in time intervals of 13 wk in Fig. 2Go.


Figure 2
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  		FIG. 2. Percentage of subjects who experienced at least one occurrence of vaginal bleeding/spotting, as assessed at each 3-monthly visit in the AST population.

 
Vaginal bleeding was reported as an AE by significantly (P < 0.001) fewer tibolone-treated subjects (3.2% with 1.25 mg and 4.1% with 2.5 mg) than CEE/MPA-treated subjects (11.6%) during the entire study period. This significant (P < 0.001) difference was also observed when the percentage of women who discontinued the study prematurely due to vaginal bleeding with tibolone (0.4% with 1.25 mg and 1.0% with 2.5 mg) was compared with the CEE/MPA group (5.5%).

Breast pain pattern

During the first 6 months of treatment, incidence of breast pain was significantly higher in the CEE/MPA group (9.7%) than the different tibolone groups (P < 0.001). Incidence in the tibolone groups was 2.8% (1.25 mg), 2.5% (2.5 mg), and 2.6% (combined). Breast pain incidence was 12.7% for the CEE/MPA group and 4.3% in both tibolone groups combined (P < 0.001). Dropout rate due to breast pain was significantly higher in the CEE/MPA group (0.9%) during the entire treatment period, compared with the tibolone groups: 0.3, 0.1, and 0.2% for the 1.25, 2.5, and combined groups, respectively.

Other common drug-related AEs

The following other common drug-related AEs were observed in the combined tibolone group and CEE/MPA group: gastrointestinal/abdominal pain (6.1 and 5.5%, respectively), weight increase (7.6 and 4.9%, respectively), and vaginal discharge (2.9 and 1.7%, respectively).

Adjudicated serious AEs

The following cardiovascular events were adjudicated by the independent cardiovascular adjudication committee: myocardial infarction, stroke, venous thromboembolism, and pulmonary embolism. In total, two adjudicated cardiovascular events have been observed in the combined tibolone groups vs. eight in the CEE/MPA group (Table 5Go). These findings regarding cardiovascular events are reassuring, but no statistical analysis was performed on the data because these events are rare and the study was not designed to evaluate adverse outcomes between groups.


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  		TABLE 5. Incidence of cardiovascular AEs in THEBES (AST group)

 
Breast cancers and other gynecological cancers have been adjudicated by the independent Breast and Gynecological Cancer Adjudication Committee: 18 breast cancers have been confirmed, 10 in the combined tibolone group and eight in the CEE/MPA group. Three breast cancers in the combined tibolone group were not confirmed by the adjudication committee; one was a ductal carcinoma in situ, and for the two others, the adjudication committee considered the translated pathology/cytology reports as inadequate to make a definitive assessment. Three ovarian cancers were confirmed, two in the combined tibolone group and one in the CEE/MPA group. One cervical carcinoma was confirmed in the CEE/MPA group.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Estrogen therapy alone increases the risk of endometrial hyperplasia and cancer, an effect that can be reversed by the addition of a progestogen in nonhysterectomized women (25, 26). This has been confirmed in numerous large clinical trials using a variety of estrogen and progestogen combinations, the most widely studied of which is CEE plus MPA (27, 28, 29, 30, 31).

The mechanism of action of tibolone is supportive for the observation that tibolone does not stimulate the endometrium. Estrogenic activity in the endometrium during tibolone treatment is reduced and counteracted by the following two mechanisms: tibolone deactivates estrogenic compounds and by stimulating the formation of biologically inactive sulfated compounds in the endometrium (11). The two estrogenic 3-hydroxytibolone metabolites are converted in the endometrium into tibolone and the progestoenic {Delta}-4 isomer (7, 8, 32). Both tibolone and {Delta}-4 isomer bind and activate the progesterone receptor and thus protect the endometrium from agonist effects of any remaining 3-OH metabolites (33).

THEBES is a very large 2-yr comparative study with the objective to confirm endometrial safety of tibolone in postmenopausal women. Endometrial hyperplasia occurred in two women receiving CEE/MPA and did not occur in those given tibolone. There were no cases of endometrial carcinoma in either group, although one woman developed an endometrial stromal sarcoma during treatment with CEE/MPA. Incidence of atrophic/inactive endometrium at the end of the study was higher in the combined tibolone than in the CEE/MPA group (87.8 vs. 79.8%), whereas proliferative, secretory and menstrual endometrium were more common with CEE/MPA. There were slightly fewer endometrial polyps in tibolone users, compared with CEE/MPA users during the first year of the study, whereas the incidence was comparable during the second year. Mean double-wall endometrial thickness was similar in all groups at all assessments, ranging from 3.0 to 3.7 mm. These data should be interpreted in the context that the study protocol was only 2 yr in duration.

Atrophic endometrium was observed in 98.2% of participants after 1 yr and 91.9% after 2 yr in a 2-yr open label study in 150 postmenopausal women given tibolone 2.5 mg daily (15). A weakly proliferative pattern was seen in the remaining women, except one woman who had simple hyperplasia after 2 yr. Such an endometrial pattern is similar to that seen in untreated women, or those given placebo, in clinical trials assessing endometrial histology (10). Endometrial thickness in women using tibolone was similar to that in women treated with various EPT regimens including oral continuous combined estradiol/norethisterone acetate in comparative studies, (14) and oral or transdermal estradiol sequentially combined with dydrogesterone (17). In contrast to EPT, add-back therapy with tibolone in women receiving GnRH agonists does not increase the size or volume of myomas (9, 34), and tibolone has been used safely and effectively as add-back therapy in women with endometriosis (35).

The endometrial safety of tibolone has been questioned after a report from the Million Women Study showing an increased risk of endometrial cancer in women with last use of tibolone or estrogen alone (36). The Million Women Study recruited 716,738 women in the United Kingdom between 1996 and 2001, approximately 45% of whom had used hormone therapy (HT) at some stage. After publication of the breast cancer results, the validity of the methodology of this study was questioned by many publications (37, 38), thus making it difficult to interpret the findings on endometrial cancer (39). Many women will have changed the type or dose of HT in the past, and it is well known that the risk of endometrial abnormalities with unopposed estrogen persists after cessation of use. Tibolone appears to be selectively prescribed to women at increased risk of both endometrial and breast cancer. Women who were prescribed tibolone were more likely to have a prior history of unopposed estrogen use, uterine surgery, and dysfunctional uterine bleeding than those prescribed EPT (40). Similar criticisms to those directed to the Million Women Study apply to a U.K. case-control study that reported an increased risk of endometrial cancer with tibolone compared with EPT (41). This finding was based on just 43 cases, and the authors admit that residual bias and uncontrolled confounding factors cannot be excluded and that the follow-up time was insufficient to draw any firm conclusions. Data from these observational and case-control studies should be regarded in the context of their limitations and potential bias, especially because they are not supported by evidence from randomized, double-blind, controlled trials.

Breast cancer was the most frequently reported gynecological cancer in the THEBES study. Any comparison between the two active groups will be complicated by the fact that CEE/MPA, in contrast to tibolone (42), is known to increase mammographic density (43). This may result in detection bias, which has also been observed in the Women’s Health Initiative trial in which incidence of breast cancer was lower during the first two years in the CEE/MPA group (38 cases) than the placebo group (51 cases) (44). Incidence of cardiovascular events is low in the tibolone group (two events), compared with the CEE/MPA group (eight events). Absence of thromboembolism (no cases with tibolone vs. three in CEE/MPA) may distinguish between estrogen-based compounds and tibolone, which is supported by effects of these compounds on the hemostasis system (45).

Tolerability of tibolone and CEE/MPA has been investigated by the two major gynecological side effects: vaginal bleeding and breast pain.

The vaginal bleeding profile of tibolone showed a marked advantage over that of CEE/MPA, with 75% of subjects experiencing no bleeding/spotting at any time, compared with 45% with CEE/MPA. Few women experienced spotting only, whereas bleeding occurred in 17% of tibolone users and 43% CEE/MPA. The incidence of vaginal bleeding reported as an AE or reason for discontinuation was significantly greater with CEE/MPA. Similar findings have been observed in previous studies comparing tibolone and CEE/MPA (46, 47, 48). One study (48), involving 501 women, showed significantly fewer women experienced bleeding with tibolone 2.5 mg than CEE/MPA during the first three cycles (23.1 vs. 40.6%; P = 0.002) and the second three cycles (15.0 vs. 26.9%; P = 0.004). Significantly less vaginal bleeding has also been reported in studies comparing tibolone 2.5 mg with another continuously combined EPT regimen, 17ß-estradiol plus norethisterone acetate (14, 49), with fewer bleeding episodes and bleeding-related discontinuations occurring with tibolone.

Breast pain was significantly less in the tibolone groups (2.3%) than the CEE/MPA group (9.7%). A similar difference has been observed in trials comparing tibolone with continuous combined estrogen plus progestin (42, 46, 48, 49).

In conclusion, the results of THEBES confirm previous clinical findings that tibolone has an acceptable safety profile, and no evidence of endometrial hyperplasia or carcinoma was observed in this 2-yr study. Tibolone caused less vaginal bleeding and less breast pain than CEE/MPA.


   Acknowledgments
 
The authors thank the THEBES investigators for their assistance in conducting this study and the subjects and their families for their willing participation in this research. The authors also thank Sylvia Engelen and Lev Sverdlov (Biometrics Department, Organon USA, Inc.) for the statistical analyses of the data. The THEBES Group participants are listed in the Appendix, which is published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org. All authors had access to the raw data and critically reviewed these as part of advising on subsequent intellectual condensation and translation before final editing and approval of the manuscript content.


   Footnotes
 
The THEBES study was supported by NV Organon, Oss, The Netherlands (Protocol 32972). NV Organon funded the study, contributed to its design, oversaw quality control at the clinical centers including periodic site visits, and validated the data collected by the centers. The sponsor did not have access to the blinding code and played no role in collecting or adjudicating disease outcomes. The sponsor prepared the first draft of the manuscript.

Disclosure Summary: D.F.A., A.F., J.C.G., S.H., J.R., and S.S. are consultants, and they have received lecture fees and grant support from Organon. F.A.H., W.d.H., and V.S. are employees of Organon.

First Published Online December 27, 2006

1 For members of the THEBES Study Group, see the Appendix published as supplemental data at http://jcem.endojournals.org. Back

Abbreviations: AE, Adverse event; AST, all subjects treated; CEE, conjugated equine estrogen; CI, confidence interval; EPT, estrogen-progestogen therapy; HT, hormone therapy; ITT, intention to treat; MPA, medroxyprogesterone acetate; THEBES, Tibolone Histology of the Endometrium and Breast Endpoints Study; TVUS, transvaginal ultrasonography.

Received October 18, 2006.

Accepted December 14, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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