Fertility and Sterility
Volume 88, Issue 4 , Pages 866-878 , October 2007

Tibolone histology of the endometrium and breast endpoints study: design of the trial and endometrial histology at baseline in postmenopausal women

  • David F. Archer, M.D.

      Affiliations

    • Department of Obstetrics and Gynecology, Contraceptive Research and Development Program Clinical Research Center, Eastern Virginia Medical School, Norfolk, Virginia
    • Corresponding Author InformationReprint requests: David F. Archer, M.D., Eastern Virginia Medical School, CONRAD Clinical Research Center, 601 Colley Avenue, Norfolk, Virginia 23507 (FAX: 757-446-8988).
    • ,
  • Susan Hendrix, D.O.

      Affiliations

    • Wayne State University/Hutzel Women's Hospital, Detroit, Michigan
    • ,
  • Alex Ferenczy, M.D.

      Affiliations

    • McGill University and Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada
    • ,
  • Juan Felix, M.D.

      Affiliations

    • Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California
    • ,
  • J. Chris Gallagher, M.D.

      Affiliations

    • Bone Metabolism Section, Creighton University Medical Center, Omaha, Nebraska
    • ,
  • Janice Rymer, M.D., Ph.D.

      Affiliations

    • King's College School of Medicine at Guy's and St. Thomas' Hospitals, Division of Obstetrics and Gynaecology, London, United Kingdom
    • ,
  • Sven O. Skouby, M.D.

      Affiliations

    • Department of Obstetrics and Gynecology, Frederiksberg Hospital, Copenhagen, Denmark
    • ,
  • Wil den Hollander, Ph.D.

      Affiliations

    • NV Organon, Oss, the Netherlands
    • ,
  • Victoria Stathopoulos, Ph.D.

      Affiliations

    • Organon International, Roseland, New Jersey
    • ,
  • Frans A. Helmond, Ph.D.

      Affiliations

    • Organon International, Roseland, New Jersey
    • ,
  • THEBES Study Group

Received 26 May 2006 ,Revised 27 December 2006 ,Accepted 27 December 2006.

References 

  1. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85:304–313
  2. Lethaby A, Suckling J, Barlow D, Farquhar CM, Jepson RG, Roberts H. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev. 2004;(3):CD000402
  3. Gambacciani M, Monteleone P, Sacco A, Genazzani AR. Hormone replacement therapy and endometrial, ovarian and colorectal cancer. Best Pract Res Clin Endocrinol Metab. 2003;17:139–147
  4. Van Gorp T, Neven P. Endometrial safety of hormone replacement therapy: review of literature. Maturitas. 2002;42:93–104
  5. Pickar JH, Thorneycroft I, Whitehead M. Effects of hormone replacement therapy on the endometrium and lipid parameters: a review of randomized clinical trials, 1985 to 1995. Am J Obstet Gynecol. 1998;178:1087–1099
  6. Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA. 2003;290:1739–1748
  7. Panay N, Studd J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update. 1997;3:159–171
  8. Genazzani AR, Monteleone P, Gambacciani M. Hormonal influence on the central nervous system. Maturitas. 2002;43(Suppl. 1):S11–S17
  9. Zweifel JE, O'Brien WH. A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology. 1997;22:189–212
  10. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003;289:3243–3253
  11. Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO, Persson I. Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy. Int J Cancer. 1999;81:339–344
  12. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92:328–332
  13. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000;283:485–491
  14. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–427
  15. Smith CL, O'Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004;25:45–71
  16. Markiewicz L, Gurpide E. In vitro evaluation of estrogenic, estrogen antagonistic and progestagenic effects of a steroidal drug (Org OD-14) and its metabolites on human endometrium. J Steroid Biochem. 1990;35:535–541
  17. Tang B, Markiewicz L, Kloosterboer HJ, Gurpide E. Human endometrial 3 beta-hydroxysteroid dehydrogenase/isomerase can locally reduce intrinsic estrogenic/progestagenic activity ratios of a steroidal drug (Org OD 14). J Steroid Biochem Mol Biol. 1993;45:345–351
  18. de Gooyer ME, Deckers GH, Schoonen WG, Verheul HA, Kloosterboer HJ. Receptor profiling and endocrine interactions of tibolone. Steroids. 2003;68:21–30
  19. de Gooyer ME, Kleyn GT, Smits KC, Ederveen AG, Verheul HA, Kloosterboer HJ. Tibolone: a compound with tissue specific inhibitory effects on sulfatase. Mol Cell Endocrinol. 2001;183:55–62
  20. Cline JM, Register TC, Clarkson TB. Comparative effects of tibolone and conjugated equine estrogens with and without medroxyprogesterone acetate on the reproductive tract of female cynomolgus monkeys. Menopause. 2002;9:242–252
  21. Genazzani AR, Benedek-Jaszmann LJ, Hart DM, Andolsek L, Kicovic PM, Tax L. Org OD 14 and the endometrium. Maturitas. 1991;13:243–251
  22. Volker W, Coelingh Bennink HJ, Helmond FA. Effects of tibolone on the endometrium. Climacteric. 2001;4:203–208
  23. Wender MC, Edelweiss MI, Campos LS, de Castro JA, Spritzer PM. Endometrial assessment in women using tibolone or placebo: 1-year randomized trial and 2-year observational study. Menopause. 2004;11:423–429
  24. Bruce D, Robinson J, Rymer J. Long-term effects of tibolone on the endometrium as assessed by bleeding episodes, transvaginal scan and endometrial biopsy. Climacteric. 2004;7:261–266
  25. Hanggi W, Bersinger N, Altermatt HJ, Birkhauser MH. Comparison of transvaginal ultrasonography and endometrial biopsy in endometrial surveillance in postmenopausal HRT users. Maturitas. 1997;27:133–143
  26. Doren M, Rubig A, Coelingh Bennink HJ, Holzgreve W. Impact on uterine bleeding and endometrial thickness: tibolone compared with continuous combined estradiol and norethisterone acetate replacement therapy. Menopause. 1999;6:299–306
  27. de Vries CS, Bromley SE, Thomas H, Farmer RD. Tibolone and endometrial cancer: a cohort and nested case-control study in the UK. Drug Saf. 2005;28:241–249
  28. Beral V, Bull D, Reeves G. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005;365:1543–1551
  29. Wierik EJ, Hendricks PT, Boerstoel-Streefland M. Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus study. Climacteric. 2004;7:197–209
  30. Landgren MB, Bennink HJ, Helmond FA, Engelen S. Dose-response analysis of effects of tibolone on climacteric symptoms. BJOG. 2002;109:1109–1114
  31. Gallagher JC, Baylink DJ, Freeman R, McClung M. Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dose-finding studies. J Clin Endocrinol Metab. 2001;86:4717–4726
  32. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321–333
  33. Pickar JH, Yeh I, Wheeler JE, Cunnane MF, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;76:25–31
  34. The Writing Group for the PEPI Trial . Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;275:370–375
  35. Pickar JH, Yeh IT, Wheeler JE, Cunnane MF, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Fertil Steril. 2003;80:1234–1240
  36. US Food and Drug Administration. Guidance for clinical evaluation of combination estrogen/progestin-containing drug products used for hormone replacement therapy of postmenopausal women. Research, FCfDEa, Editor. 1995.
  37. Committee for Proprietary Medicinal Products. Points to consider on hormone replacement therapy. CPMP/EWP/021/97. London, 1997.
  38. Sherman M, Mazur M, Kurman R. Benign diseases of the endometrium. In:  Kurman R editors. Blaustein's pathology of the female genital tract. New York: Springer; 2002;p. 421–466
  39. Ronett B, Kurman R. Precursor lesions of endometrial carcinoma. In:  Kurman R editors. Blaustein's pathology of the female genital tract. New York: Springer; 2002;p. 467–500
  40. American College of Radiology . Illustrated Breast Imaging Reporting and Datasystems (BI-RADS). 3rd ed.. Reston, VA: American College of Radiology; 1998;
  41. Byng JW, Yaffe MJ, Jong RA, Shumak RS, Lockwood GA, Tritchler DL, et al. Analysis of mammographic density and breast cancer risk from digitized mammograms. Radiographics. 1998;18:1587–1598
  42. Wiklund I, Karlberg J, Mattsson LA. Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: a double-blind placebo-controlled study. Am J Obstet Gynecol. 1993;168:824–830
  43. Hunter M. The Women's Health Questionnaire: a measure of mid-aged women's perceptions of their emotional and physical health. Psychol Health. 1992;7:45–54
  44. McCoy NL, Davidson JM. A longitudinal study of the effects of menopause on sexuality. Maturitas. 1985;7:203–210
  45. McCoy NL. Methodological problems in the study of sexuality and the menopause. Maturitas. 1998;29:51–60
  46. Legault C, Espeland MA, Wasilauskas CH, Bush TL, Trabal J, Judd HL, et al. Agreement in assessing endometrial pathology: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Womens Health. 1998;7:435–442
  47. Archer DF, McIntyre-Seltman K, Wilborn WW, Dowling EA, Cone F, Creasy GW, et al. Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol. 1991;165:317–320
  48. Korhonen MO, Symons JP, Hyde BM, Rowan JP, Wilborn WH. Histologic classification and pathologic findings for endometrial biopsy specimens obtained from 2964 perimenopausal and postmenopausal women undergoing screening for continuous hormones as replacement therapy (CHART 2 Study). Am J Obstet Gynecol. 1997;176:377–380

 The THEBES Study Group participants are listed in the Appendix.

 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 first draft of the manuscript has been prepared by an independent medical writing group. D.F.A., S.H., A.F., J.C.G., J.R., and S.O.S. are consultants and have received lecture fees and grant support from Organon. J.F. has a contractual relationship with Organon for this study. W.d.H., V.S., and F.A.H. are employees of Organon.

PII: S0015-0282(07)00098-2

doi: 10.1016/j.fertnstert.2006.12.052

Fertility and Sterility
Volume 88, Issue 4 , Pages 866-878 , October 2007

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