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Clinical Response, Vascular Change, and Angiogenesis in Gonadotropin-Releasing Hormone Analogue-Treated Women With Uterine Myomas

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Abstract

Objective

Basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) are involved in the pathogenesis of leiomyomas and influence angiogenesis, which is necessary for growth of leiomyomas. Gonadotropin-releasing hormone analogue (GnRH-a) treatment might modify the growth factor expression and the blood supply in myomas. We investigated the effects of GnRH-a treatment on some clinical parameters, on the immunohistochemical expression of bFGF, VEGF, and PDGF, and on the vasculature of leiomyomas.

Methods

Thirty-one women were treated with leuprolide acetate for 3 months; 55 untreated patients formed the control group. Hematologic parameters were assessed at the admission, after GnRH-a treatment, and after surgery. Uterine volume was evaluated by ultrasonography. The immunoexpression of bFGF, VEGF, and PDGF and of the endothelial markers CD34 and CD105, as well as the vascular pattern, were studied in leiomyomas, comparing treated and untreated patients.

Results

Hematologic parameters improved and uterine volumes decreased after GnRH-a treatment. The immunoexpression of bFGF, VEGF, and PDGF decreased in treated myomas, together with the total number of vessels and the angiogenetic vessels.

Conclusion

This study confirms the clinical response of uterine shrinkage after GnRH-a treatment. A pathogenetic role of bFGF, VEGF, and PDGF in myoma growth and vascularization is suggested. Finally, this study indirectly confirms the importance of the vasculature in leiomyoma growth.

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References

  1. Vollenhoven BJ, Healy DL. Pathophysiology and medical treatment of uterine fibroids. In: Cameron IT, Fraser IS, Smith SK, eds. Clinical Disorders of the Endometrium and Menstrual Cycle. Oxford: Oxford University Press, 1998:207–18.

    Google Scholar 

  2. Lethaby A, Vollenhoven B, Sowter M. Efficacy of pre-operative gonadotropin hormone releasing analogues for women with uterine fibroids undergoing hysterectomy or myomectomy: A systematic review. Br J Obstet Gynaecol 2002;109:1097–108.

    Article  CAS  Google Scholar 

  3. Andersen J. Factors in fibroid growth. Baillieres Clin Obstet Gynaecol 1998;12:225–43.

    CAS  PubMed  Google Scholar 

  4. Harrison-Woolrych ML, Charnock DS, Smith SK. Quantification of messenger ribonucleic acid for epidermal growth factor in human myometrium and leiomyomata using reverse transcription polymerase chain reaction. J Clin Endocrinol Metab 1994;78:1179–84.

    CAS  PubMed  Google Scholar 

  5. Englund K, Lindblom B, Carlström K, Gustavsson I, Sjöblom P, Blanck A. Gene expression and tissue concentrations of IGF-I in human myometrium and fibroids under different hormonal conditions. Mol Hum Reprod 2000;6:915–20.

    Article  CAS  PubMed  Google Scholar 

  6. Stewart EA, Nowak RA. Clinical commentary: new concepts in the treatment of uterine leiomyomas. Obstet Gynecol 1998;4:624–7.

    Google Scholar 

  7. Barbarisi A, Perillo O, Di Lieto A, et al. 17-β Estradiol elicits an autocrine leiomyoma cell proliferation: Evidence for a stimulation of protein kinase-dependent pathway. J Cell Physiol 2001;186:414–24.

    Article  CAS  PubMed  Google Scholar 

  8. Di Lieto A, De Rosa G, De Falco M, et al. Relationship between platelet-derived growth factor expression in leiomyomas and uterine volume changes after gonadotropin-releasing hormone agonist treatment. Hum Pathol 2002;33:220–4.

    Article  PubMed  Google Scholar 

  9. Dixon D, Hong H, Haseman JK. Immnohistochemical localization of growth factors and their receptors in uterine leiomyomas and matched myometrium. Environ Health Perspect 2000;108(Suppl 5):795–802.

    Article  CAS  PubMed  Google Scholar 

  10. Wu X, Blanck A, Olovsson M, Möller B, Linblom B. Expression of basic fibroblast growth factor (bFGF), FGF receptor 1 and FGF receptor 2 in uterine leiomyomas and myometrium during the menstrual cycle, after menopause and GnRHa treatment. Acta Obstet Gynecol Scand 2001;80:497–504.

    Article  CAS  PubMed  Google Scholar 

  11. Anania CA, Stewart EA, Quade BJ, Hill JA, Nowak RA. Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal uterine bleeding. Mol Hum Pathol 1997;3:685–91.

    CAS  Google Scholar 

  12. Werner R. Mechanisms of angiogenesis. Nature 1997;386:671–4.

    Article  Google Scholar 

  13. Goto F, Goto K, Weindel K, Folkman J. Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest 1993;69:508–71.

    CAS  PubMed  Google Scholar 

  14. Tsai JC, Goldman CK, Gillespie GY. Vascular endothelial growth factor in human glioma cell lines: Induced secretion by EGF, PDGF-BB and bFGF. J Neurosurg 1995;82:864–73.

    Article  CAS  PubMed  Google Scholar 

  15. Ferrara N, Houck K, Jakeman L, Leung DW. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 1992;13:18–32.

    Article  CAS  PubMed  Google Scholar 

  16. Harrison-Woolrych ML, Sharkey AM, Charnock DS, Smith SK. Localization and quantification of vascular endothelial growth factor messenger ribonucleic acid in human myometrium and leiomyomata. J Clin Endocrinol Metab 1995;80:1853–8.

    CAS  PubMed  Google Scholar 

  17. Stewart EA, Nowak RA. Leiomyoma-related bleeding: A classic hypothesis updated for the molecular era. Hum Reprod Update 1996;2:295–306.

    Article  CAS  PubMed  Google Scholar 

  18. Abulafia O, Kleinhaus K, Levi G, Lee YC, Sherer DM. Effect of gonadotropin-releasing hormone agonist treatment upon angiogenesis in uterine leiomyoma. Gynecol Obstet Invest 2001;52:108–13.

    Article  CAS  PubMed  Google Scholar 

  19. Rutgers JL, Spong CY, Sinow R, Heiner J. Leuprolide acetate treatment and myoma arterial size. Obstet Gynecol 1995;86:386–8.

    Article  CAS  PubMed  Google Scholar 

  20. Demopoulos R, Jones KJ, Mittal KR, Vamavakas EC. Histology of leiomyomata in patients treated with leuprolide acetate. Int J Gynecol Pathol 1997;16:131–7.

    Article  CAS  PubMed  Google Scholar 

  21. Colgan TJ, Pendergast S, LeBlanc M. The histopathology of uterine leiomyomas following treatment with gonadotropin-releasing hormone analogues. Hum Pathol 1993;24:1073–7.

    Article  CAS  PubMed  Google Scholar 

  22. Detre S, Saccani Jotti G, Dowsett MA. “quickscore” method for immunohistochemical semiquantitation: Validation for oestrogen receptor in breast carcinomas. J Clin Pathol 1995;48:876–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fontanini G, Faviana P, Lucchi M, et al. A high vascular count and overexpression of vascular endothelial growth factor are associated with unfavourable prognosis in operated small cell lung carcinoma. Br J Cancer 2002;86:558–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Friedman AJ. Treatment of uterine myomas with GnRH agonists. Semin Reprod Endocrinol 1993;11:154–61.

    Article  Google Scholar 

  25. Deligdisch L, Hirschmann S, Altchek A. Pathologic changes in gonadotropin releasing hormone agonist analogue treated uterine leiomyomata. Fertil Steril 1997;67:837–41.

    Article  CAS  PubMed  Google Scholar 

  26. Kawamura N, Ito F, Ichimura T, Shibata S, Umesaki N, Ogita S. Correlation between shrinkage of uterine leiomyoma treated with buserelin acetate and histopathologic findings of biopsy specimen before treatment. Fertil Steril 1997;68:632–6.

    Article  CAS  PubMed  Google Scholar 

  27. Mizutani T, Sugihara A, Nakamuro K, Terada N. Suppression of cell proliferation and induction of apoptosis in uterine leiomyoma by gonadotropin-releasing hormone agonist (leuprolide acetate). J Clin Endocrinol Metab 1998;84:1253–5.

    Article  Google Scholar 

  28. Vu K, Greenspan DL, Wu TC, Zacur HA, Kurman RJ. Cellular proliferation, estrogen receptor, progesterone receptor, and bcl-2 expression in GnRH-agonist-treated uterine leiomyomas. Hum Pathol 1998;29:359–63.

    Article  CAS  PubMed  Google Scholar 

  29. Crow J, Gardner RL, Sweeney G, Shaw RW. Morphological changes in uterine leiomyomas treated by GnRH agonist gos-erelin. Int J Gynecol Pathol 1995;14:235–42.

    Article  CAS  PubMed  Google Scholar 

  30. Sreenan JJ, Prayson RA, Biscotti CV, Thornton MH, Eawsley KA, Hart WR. Histopathologic findings in 107 uterine leiomyomas treated with leuprolide acetate compared with 126 controls. Am J Surg Pathol 1996;20:427–32.

    Article  CAS  PubMed  Google Scholar 

  31. Reinsch RC, Murphy AA, Morales AJ, Yen SS. The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: A prospective, randomized study. Am J Obstet Gynecol 1994;170:1623–8.

    Article  CAS  PubMed  Google Scholar 

  32. Nowak RA. Identification of new therapies for leiomyomas: What in vitro studies can tell us. Clin Obstet Gynecol 2001;44:327–34.

    Article  CAS  PubMed  Google Scholar 

  33. Cordon-Cardo C, Vlodasky I, Haimovitz-Friedman A, Hicklin D, Fuks Z. Expression of basic fibroblasr growth factor in normal human tissues. Lab Invest 1990;63:832–40.

    CAS  PubMed  Google Scholar 

  34. Battegay EJ. Angiogenesis. Mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med 1995;37:333–46.

    Google Scholar 

  35. Presta M. Sex hormones modulate the synthesis of basic fibroblast growth factor in human endometrial adenocarcinoma cells: Implications for the neovascularization of normal and neoplastic endometrium. J Cell Physiol 1988;137:593–7.

    Article  CAS  PubMed  Google Scholar 

  36. Lindner V, Reidy MA. Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Proc Natl Acad Sci USA 1998;88:3739–43.

    Article  Google Scholar 

  37. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors FASEB J 1999;13:9–22.

    Article  CAS  PubMed  Google Scholar 

  38. Esser S, Wolburg K, Wolburg H, Breier G, Kurzchalia T, Risau W. Vascular endothelial growth factor induces endothelial fenestrations in vitro. J Cell Biol 1998;140:947–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Taniguchi Y, Morita I, Kubota T, Murota S, Aso T. Human uterine myometrial smooth muscle cell proliferation and vascular endothelial growth-factor production in response to platelet-derived growth factor. J Endocrinol 2001;169:78–86.

    Article  Google Scholar 

  40. Mangrulkar RS, Ono M, Ishikawa M, Takashima S, Klagsbrun M, Nowak RA. Isolation and characterization of heparin-binding growth factors in human leiomyomas and normal myometrium. Biol Reprod 1995;53:636–46.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrical-Gynaecological and Urological Science and Reproductive Medicine, University “Federico II” of Naples, Napoli, Italy

    Andrea Di Lieto MD, PhD, Marianna De Falco MD, Fabrizio Pollio MD, Gelsomina Mansueto MD, Gaetano Salvatore MD, Pasquale Somma MD, Francesca Ciociola MD, Gaetano De Rosa MD, PhD & Stefania Staibano MD

  2. Department of Biomorphological and Functional Science, University “Federico II” of Naples, Napoli, Italy, Via L. Giordano, 120, 80127

    Andrea Di Lieto MD, PhD, Marianna De Falco MD, Fabrizio Pollio MD, Gelsomina Mansueto MD, Gaetano Salvatore MD, Pasquale Somma MD, Francesca Ciociola MD, Gaetano De Rosa MD, PhD & Stefania Staibano MD

Authors
  1. Andrea Di Lieto MD, PhD
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  2. Marianna De Falco MD
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  3. Fabrizio Pollio MD
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  8. Gaetano De Rosa MD, PhD
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  9. Stefania Staibano MD
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Corresponding author

Correspondence to Andrea Di Lieto MD, PhD.

Additional information

This work was supported by Grant 2002/061134 of the Italian Ministry of University and Scientific Research. Special acknowledgment goes to Simona De Falco for the linguistic revision of the manuscript.

A. Di Lieto and M. De Falco equally contributed to this work.

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Di Lieto, A., De Falco, M., Pollio, F. et al. Clinical Response, Vascular Change, and Angiogenesis in Gonadotropin-Releasing Hormone Analogue-Treated Women With Uterine Myomas. Reprod. Sci. 12, 123–128 (2005). https://doi.org/10.1016/j.jsgi.2004.10.008

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