American Journal of Obstetrics & Gynecology
Volume 202, Issue 5 , Pages 485.e1-485.e9 , May 2010

Effect of hormone replacement and selective estrogen receptor modulators (SERMs) on the biomechanics and biochemistry of pelvic support ligaments in the cynomolgus monkey (Macaca fascicularis)

Presented in part at the 34th Annual Scientific Meeting of the Society of Gynecologic Surgeons, Savannah, GA, April 12-17, 2008, and in full at the 30th Annual Scientific Meeting of the American Urogynecologic Society, Hollywood, FL, Sept. 24-26, 2009.

  • Azin Shahryarinejad, MD, MPH

      Affiliations

    • Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Keck School of Medicine at USC, Los Angeles, CA
    • ,
  • Thomas R. Gardner, MCE

      Affiliations

    • Center for Orthopaedic Research, Department of Orthopaedic Surgery, Columbia University College of Physicians and Surgeons, New York, NY
    • ,
  • J. Mark Cline, DVM, PhD

      Affiliations

    • Section on Comparative Medicine, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC
    • ,
  • William N. Levine, MD

      Affiliations

    • Center for Orthopaedic Research, Department of Orthopaedic Surgery, Columbia University College of Physicians and Surgeons, New York, NY
    • ,
  • Haley A. Bunting, MS

      Affiliations

    • Center for Orthopaedic Research, Department of Orthopaedic Surgery, Columbia University College of Physicians and Surgeons, New York, NY
    • ,
  • Michael D. Brodman, MD

      Affiliations

    • Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Mount Sinai School of Medicine, New York, NY
    • ,
  • Charles J. Ascher-Walsh, MD

      Affiliations

    • Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Mount Sinai School of Medicine, New York, NY
    • ,
  • Richard J. Scotti, MD

      Affiliations

    • Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Keck School of Medicine at USC, Los Angeles, CA
    • ,
  • Michael D. Vardy, MD

      Affiliations

    • Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Mount Sinai School of Medicine, New York, NY

Received 4 August 2009 ,Revised 10 November 2009 ,Accepted 24 January 2010.

References 

  1. DeLancey JOL. The anatomy of the pelvic floor. Curr Opin Obstet Gynecol. 1994;6:313–316
  2. Norton PA. Pelvic floor disorders: the role of fascia and ligaments. Clin Obstet Gynecol. 1993;36:926–938
  3. Chen GD, Oliver RH, Leung BS, Lin LY, Yeh J. Estrogen receptor alpha and beta expression in the vaginal walls and uterosacral ligaments of premenopausal and postmenopausal women. Fertil Steril. 1999;71:1099–1102
  4. Mokrzycki ML, Mittal K, Smilen SW, Blechman AN, Porges RF, Demopolous RI. Estrogen and progesterone receptors in the uterosacral ligament. Obstet Gynecol. 1997;90:402–404
  5. Goh JTW. Biomechanical properties of prolapsed vaginal tissue in pre and post menopausal women. Int Urogynecol J. 2002;13:76–79
  6. Reay-Jones NH, Healy JC, King LJ, Saini S, Shousha S, Allen-Mersh TG. Pelvic connective tissue resilience decreases with vaginal delivery, menopause and uterine prolapse. Br J Surg. 2003;90:466–472
  7. Kökçü A, Yanik F, Çetinkaya M, Alper T, Kandemir B, Malatyalioglu B. Histopathological evaluation of the connective tissue of the vaginal fascia and the uterine ligaments in women with and without pelvic relaxation. Arch Gynecol Obstet. 2002;266:75–78
  8. Goh JTW. Biochemical and biochemical assessments for pelvic organ prolapse. Curr Opin Obstet Gynecol. 2003;15:391–394
  9. Kim CM, Jeon MJ, Chung DJ, Kim SK, Kim JW, Bai SW. Risk factors for pelvic organ prolapsed. Int J Gynecol Obstet. 2007;98:248–251
  10. Brown JS, Grady D, Ouslander JG, Herzog AR, Varner RE, Posner SF. Prevalence of urinary incontinence and associated risk factors in postmenopausal women (Heart and Estrogen/Progestin Replacement Study (HERS) Research Group). Obstet Gynecol. 1999;94:66–70
  11. Akizuki S, Mow VC, Müller F, Pita JC, Howell DS, Manicourt DH. Tensile properties of human knee joint cartilage: I, influence of ionic conditions, weight bearing, and fibrillation on the tensile modulus. J Orthop Res. 1986;4:379–392
  12. Rasanen T, Messner K. Estrogen-dependent tensile properties of the rabbit knee medial collateral ligament. Scand J Med Sci Sports. 2000;10:20–27
  13. Vardy MD, Gardner TR, Cosman F, et al. The effects of hormone replacement on the biomechanical properties of the uterosacral and round ligaments in the monkey model. Am J Obstet Gynecol. 2005;192:1741–1751
  14. Haas JS, Kaplan CP, Gerstenberger EP, Kerlikowske K. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med. 2004;140:184–188
  15. Writing Group for the Women's Health Initiative Investigators. 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
  16. Majumdar SR, Almasi EA, Stafford RS. Promotion and prescribing of hormone therapy after report of harm by the Women's Health Initiative. JAMA. 2004;292:1983–1988
  17. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA. 2004;291:47–53
  18. Hing E, Brett KM. Changes in US prescribing patterns of menopausal hormone therapy, 2001-2003. Obstet Gynecol. 2006;108:33–40
  19. Hendrix SL, McNeeley SG. Effect of selective estrogen receptor modulators on reproductive tissues other than endometrium. Ann N Y Acad Sci. 2001;949:243–250
  20. Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial—multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat. 2001;67:191–199
  21. Vogel VG, Costantino JP, Wickerham DL, et al. National Surgical Adjuvant Breast and Bowel Project (NSABP) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727–2741
  22. Silfen SL, Ciaccia AV, Bryant HU. Selective estrogen receptor modulators: tissue selectivity and differential uterine effects. Climacteric. 1999;2:268–283
  23. Vardy MD, Lindsay R, Scotti RJ, et al. Short-term urogenital effects of raloxifene, tamoxifen, and estrogen. Am J Obstet Gynecol. 2003;189:81–88
  24. Goldstein SR, Nanavati N. Adverse events that are associated with the selective estrogen receptor modulator levormeloxifene in an aborted phase III osteoporosis treatment study. Am J Obstet Gynecol. 2002;187:521–527
  25. Warming L, Christoffersen C, Riis BJ, Stakkestad JA, Delmas PD, Christiansen C. Adverse effects of a SERM (Levormeloxifene): safety parameters and bone mineral density 12 months after treatment withdrawal. Maturitas. 2003;44:189–199
  26. Goldstein SR, Neven P, Zhou L, Taylor YL, Ciaccia AV, Plouffe L. Raloxifene effect on frequency of surgery for pelvic floor relaxation. Obstet Gynecol. 2001;98:91–96
  27. Sharma S, Albertazzi P, Bottazzi M. The long-term effect of raloxifene on the genitourinary tract. Climacteric. 2007;10:244–248
  28. Albertazzi P, Sharma S. Urogenital effects of selective estrogen receptor modulators: a systematic review. Climacteric. 2005;8:214–220
  29. 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
  30. Cline JM, Söderqvist G, Register TC, Williams JK, Adams MR, Von Schoultz B. Assessment of hormonally active agents in the reproductive tract of female nonhuman primates. Toxicol Pathol. 2001;29:84–90
  31. Sikoski P, Register TC, Lees CJ, et al. Effects of two novel selective estrogen receptor modulators, raloxifene, tamoxifen, and ethinyl estradiol on the uterus, vagina and breast in ovariectomized cynomolgus monkeys (Macaque fascicularis). Am J Obstet Gynecol. 2007;196:75–77
  32. Otto LN, Slayden OD, Clark AL, Brenner RM. The rhesus macaque as an animal model for pelvic organ prolapse. Am J Obstet Gynecol. 2002;186:416–421
  33. Shahryarinejad A, Vardy MD. Comparison of human to macaque uterosacral-cardinal ligament complex and its relationship to pelvic organ prolapse. Toxicol Pathol. 2008;6(suppl 1):101S–107S
  34. Ulfelder H. The mechanism of pelvic support in women: deductions from a study of the comparative anatomy and physiology of the structures involved. Am J Obstet Gynecol. 1956;72:856–864
  35. Weber AM, Buchsbaum GM, Chen B, et al. Basic science and translational research in female pelvic floor disorders: proceedings of an NIH-sponsored meeting. Neurourol Urodyn. 2004;23:288–301
  36. Zuker M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 2003;31:3406–3415
  37. Woo SL, Gomez MA, Akeson WH. The time and history-dependent viscoelastic properties of the canine medical collateral ligament. J Biomech Eng. 1981;103:293–298
  38. Abramowitch SD, Feola A, Jallah Z, Moalli PA. Tissue mechanics, animal models, and pelvic organ prolapse: a review. Eur J Obstet Gynecol Reprod Biol. 2009;144(Suppl 1):S146–S158
  39. Doillon CH, Dunn MG, Bender E, Silver FH. Collagen fiber formation in repair tissue: development of strength and toughness. Coll Relat Res. 1985;5:481–492
  40. Niyibizi C, Eyre DR. Structural characteristics of cross-linking sites in type V collagen of bone: chain specificities and heterotypic links to type I collagen. Eur J Biochem. 1994;224:943–950
  41. Liapis A, Bakas P, Pafiti A, et al. Changes of collagen type III in female patients with genuine stress incontinence and pelvic organ prolapse. Eur J Obstet Gynecol. 2001;97:76–79
  42. Alperin M, Moalli PA. Remodeling of vaginal connective tissue in patients with POP. Curr Opin Obstet Gynecol. 2006;18:544–550
  43. Chen BH, Wen Y, Li H, Polan ML. Collagen metabolism and turnover in women with stress urinary incontinence and pelvic organ prolapse. Int Urogynecol J. 2002;13:80–87

 Cite this article as: Shahryarinejad A, Gardner TR, Cline JM, et al. Effect of hormone replacement and selective estrogen receptor modulators (SERMs) on the biomechanics and biochemistry of pelvic support ligaments in the cynomolgus monkey (Macaca fascicularis). Am J Obstet Gynecol 2010;202:485.e1-9.

 Reprints not available from the authors.

 This study was funded by the American College of Obstetricians and Gynecologists ACOG/Solvay Research Award in Menopause. The parent study was supported in part by Johnson and Johnson Pharmaceutical Research and Development, LLC.

PII: S0002-9378(10)00104-3

doi: 10.1016/j.ajog.2010.01.074

American Journal of Obstetrics & Gynecology
Volume 202, Issue 5 , Pages 485.e1-485.e9 , May 2010

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