Tuesday, October 30, 2007
Beautiful Agony Pepper
October 31, 2007
the study tell us about endometrial Thebes?
the study tell us about endometrial Thebes?
Urdinola Jaime MD
Medical Association Andes Bogotá DC Colombia
Phone 571/215 23 00
blogger: www.urdinola.blogspot.com
Symposium / Luncheon on Women's Health
Andes Medical Association - Board Room Wednesday October
31, 2007
THEBES study 1 means an abbreviation for the Study of Endometrial Histology Tibolone on Breast and end point.
This is a multicenter (73 centers in the U.S., 69 in Europe and 4 in Chile), randomized, double-masked, which was designed to address and respond objectively to the conflicting reports have appeared in scientific literature Endometrial safety with tibolone (either with 1.25 or 2.5 mg / day). Tibolone therefore treatment was compared with continuous combined conjugated equine estrogen (CEE) and acetate medroxyprogesterone (MPA) (0.625 mg + 2.5 mg / day).
Participants in the study, average age 54.4 + 4.4 years, were randomized into 3 groups in the following ratio 1:1:2 with tibolone 1.25 mg / day, 2.5 mg / day and CEE / MPA, respectively. The confidence interval 95% (95%) were evaluated for the incidence of abnormal endometrial histology (hyperplasia or carcinoma) and hyperplasia and carcinoma separately for each treatment group and combined treatment group, after 1 and 2 years of treatment with tibolone.
were randomized to a total of 3 240 women. Of these 3 224 received at least one dose of study medication. The incidence and 95% of abnormal endometrium (hyperplasia or carcinoma) and hyperplasia and carcinoma separately, were calculated at the end points 1 and 2 years after treatment, the incidence being 0.0 (0.5), 0.0 (0.4 ) and 0.2 (0.5) respectively in the proportion that was recorded earlier. The presence of amenorrhea was reported more frequently with tibolone, throughout the study, 1.25 mg = 78.7% and 2.5 mg = 71.4%, with EEC / MPA = 44.9%.
The research team concludes that the results confirm previous findings:
- that tibolone does not induce endometrial hyperplasia or carcinoma in postmenopausal women
- that is associated with better vaginal bleeding profile than CEE / MPA
Tibolone has been used for the management of menopausal symptoms in postmenopausal women, with positive effects on mood, sexual wellness, vaginal atrophy, urogenital symptoms and bone loss, low incidence of vaginal bleeding and mastalgia. The standard dosage has been so far of 2.5 mg / day. Estrogenic effects in a tissue selective act on brain, vagina and bone but not on the breast or endometrium.
turn, tibolone on the endometrium becomes irreversibly to Δ-4 isomer that binds to receptors progesterone and androgen 2. Furthermore, tibolone and Δ-4 isomer induce enzymes that inactivate estrogens such as 17-β hydroxysteroid dehydrogenase and sulfotransferase. Sulfatase also inhibit and enhance local deactivation of active estrogen metabolites. Other studies have shown that the metabolites 3-α and 3-β hidroxitibolona progestins act as cultured human endometrial cells, probably due to intracellular conversion of these metabolites to tibolone and to the Δ-4 isomer. For this reason it is required to add a progestogen to the treatment with tibolone.
Security endometrial cancer with tibolone had been demonstrated in many previous clinical studies, which showed a high incidence of atrophic endometrium without hyperplasia and no increase in endometrial thickness compared with the administration of combined hormone therapy (estrogen + progesterone).
This was questioned following the publication of the million women study 3, although the validity of the methodology of this publication has been questioned by many publications and tibolone was prescribed more frequently and more selectively , women at increased risk for endometrial or breast cancer. No cases
carcinoma or endometrial hyperplasia in women treated with tibolone, as main finding of this study.
2 cases of endometrial hyperplasia occurred in the CEE + MPA group: one case of atypical hyperplasia 1 year, confirmed by curettage and hysteroscopy. The other case was complex hyperplasia year 2, when the participant had completed the study period. A subsequent biopsy of this last 3 months showed only atrophic endometrium.
Although no cases of endometrial carcinoma, it was a case of endometrial stromal sarcoma of low grade, in the CEE + MPA group with 1 year of treatment.
The number of polyps Endometrial was similar in the 3 groups, 33 subjects (2.6%) in the 2 groups with tibolone and 40 cases (3.10%%) in the CEE + MPA group during the first year of treatment. 24 cases (2.5%) and 25 cases (2.5%) per year 2. No cases of carcinomatous polyps, although there were hyperplastic polyps, 8 in the tibolone group and 1 in the CEE + MPA group as one of the pathologists, and only a hyperplastic polyp in the tibolone groups according to the second pathologist.
groups in any of the endometrial thickness exceeded 4 mm.
18 cases were confirmed breast cancer, 10 in the 2 groups with tibolone and 8 in the CEE + MPA group. 3 Where tibolone groups were not confirmed by the independent Adjudication Committee Breast and Gynecological Cancer. One was a ductal carcinoma in-situ and in the other 2 cases were considered inadequate cytology or pathology reports to make a definitive diagnosis.
also were confirmed 3 cases of ovarian cancer, 2 in the tibolone group and one in the other group.
A case of cervical carcinoma was confirmed in the CEE + MPA group.
In conclusion, the study THEBES faith a relatively large study, with duration of 2 years and comparative. The incidence of atrophic / inactive at the end of the study was higher in groups with tibolone than with CEE + MPA, 87.8% vs. 79.8%. Proliferative endometrium, secretory and menstrual was more frequent in the CEE + MPA group.
There were no cases of venous thromboembolism in any of the 3 groups, although it should be noted that previous use of sex steroids as contraceptive or hormone therapy was on average across groups of 67.7%.
According to these data and in conclusion, the safety profile of tibolone is acceptable, no evidence of endometrial hyperplasia or carcinoma in this study with 2 years.
Highlights
● Study Study THEBES or tibolone Endometrial Histology of Breast and as an endpoint, was a multicenter investigation in the form in 2 continents. Randomized, double-masked comparison between 2 doses of tibolone (1.25 and 2.5 mg / day) and the combination of CEE + MPA (0.625 mg + 2.5 mg / day), with randomization of 3 240 women and a proportional distribution, respectively, 1:1:2
● According to the results, tibolone does not induce endometrial hyperplasia or endometrial cancer or
● It has a better vaginal bleeding profile and a higher proportion of women in amenorrhea with treatment, the combination of CEE + MPA
● No need to add a progestogen to tibolone, as the endometrium becomes isomer Δ-4 or induce enzymes that inactivate estrogens at this level between the various mechanisms that have been reported about its effect on the endometrium
● unfavorable findings million women study on endometrium (study very much in doubt because of methodological limitations) appear to be undermined by THEBES study, relatively large study lasting 2 years
● In this study the safety profile of tibolone is acceptable, no evidence of endometrial hyperplasia or carcinoma
References 1 - Archer DF, Hendrix S, Gallagher JC, Rymer J, Skouby S, Ferenczy A, den Hollander W, Stathopoulos V and Helmond FA, for the Tibolone Histology of the Endometrium and Breast Endpoints ( THEBES ) Study Group. Endometrial Effects of Tibolone. J Clin Endocrinol Metab 2007; 92: 911-918.
2- L. J. Blok, P. E. De Ruiter, E. C. M. Kühne, E. E. Hanekamp, J. A. Grootegoed, E. Smid-Koopman, S. C. J. P. Gielen, M. E. De Gooyer, H. J. Kloosterboer and C. W. Burger. Progestagenic Effects of Tibolone on Human Endometrial Cancer Cells. J Clin Endocrinol Metab 2003; 88: 2327-2334.
3- Beral, V, BullD, Reeves G for the Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005, 365:1543-1551.
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