Contraception
Volume 79, Issue 2 , Pages 139-145 , February 2009

Effects of progesterone, levonorgestrel and medroxyprogesterone acetate on apoptosis in human endometrial endothelial cells

  • Chainarong Choksuchat

      Affiliations

    • CONRAD Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA
    • Faculty of Medicine, Department of Obstetrics and Gynecology, Prince of Songkla University, Hat-Yai, Songkhla 90110, Thailand
  • ,
  • Shumei Zhao

      Affiliations

    • CONRAD Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA
  • ,
  • Todd D. Deutch

      Affiliations

    • CONRAD Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA
  • ,
  • Thomas D. Kimble

      Affiliations

    • CONRAD Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA
  • ,
  • David F. Archer

      Affiliations

    • CONRAD Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 757 446 7444; fax: +1 757 446 8998.

Received 7 August 2008 ,Revised 27 August 2008 ,Accepted 28 August 2008.

References 

  1. Fraser IS, Hickey M. Endometrial vascular changes and bleeding disturbances with long-acting progestins. Steroids. 2000;65:665–670
  2. Hickey M, Crewe J, Mahoney LA, Doherty DA, Fraser IS, Salamonsen LA. Mechanisms of irregular bleeding with hormone therapy: the role of matrix metalloproteinases and their tissue inhibitors. J Clin Endocrinol Metab. 2006;91:3189–3198
  3. Hickey M. Bleeding with menopausal hormone therapy: physiological or pathological?. Menopause Int. 2007;13:188–190
  4. Hickey M, Dwarte D, Fraser IS. Superficial endometrial vascular fragility in Norplant users and in women with ovulatory dysfunctional uterine bleeding. Hum Reprod. 2000;15:1509–1514
  5. Hickey M, Fraser IS. Human uterine vascular structures in normal and diseased states. Microsc Res Tech. 2003;60:377–389
  6. Krikun G, Critchley H, Schatz F, et al. Abnormal uterine bleeding during progestin-only contraception may result from free radical-induced alterations in angiopoietin expression. Am J Pathol. 2002;161:979–986
  7. Vincent AJ, Zhang J, Ostor A, et al. Decreased tissue inhibitor of metalloproteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding?. Hum Reprod. 2002;17:1189–1198
  8. Freitas S, Meduri G, Le Nestour E, Bausero P, Perrot-Applanat M. Expression of metalloproteinases and their inhibitors in blood vessels in human endometrium. Biol Reprod. 1999;61:1070–1082
  9. Krikun G, Mor G, Huang J, Schatz F, Lockwood CJ. Metalloproteinase expression by control and telomerase immortalized human endometrial endothelial cells. Histol Histopathol. 2005;20:719–724
  10. Kabir J, Lobo M, Zachary I. Staurosporine induces endothelial cell apoptosis via focal adhesion kinase dephosphorylation and focal adhesion disassembly independent of focal adhesion kinase proteolysis. Biochem J. 2002;367(Pt 1):145–155
  11. Abdel-Aleem H, d'Arcangue C, Vogelsong K, Gulmezoglu AM. Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. Cochrane Database Syst Rev. 2007;(2):CD003449
  12. Livingstone M, Fraser IS. Mechanisms of abnormal uterine bleeding. Hum Reprod Update. 2002;8:60–67
  13. Hickey M, Fraser IS. The structure of endometrial microvessels. Hum Reprod. 2000;15(Suppl 3):57–66
  14. Hickey M, Simbar M, Markham R, et al. Changes in vascular basement membrane in the endometrium of Norplant users. Hum Reprod. 1999;14:716–721
  15. Krikun G, Schatz F, Taylor R, et al. Endometrial endothelial cell steroid receptor expression and steroid effects on gene expression. J Clin Endocrinol Metab. 2005;90:1812–1818
  16. Brenner RM, Slayden OD. Steroid receptors in blood vessels of the rhesus macaque endometrium: a review. Arch Histol Cytol. 2004;67:411–416
  17. Critchley HO, Brenner RM, Henderson TA, et al. Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. J Clin Endocrinol Metab. 2001;86:1370–1378
  18. Vani S, Critchley HO, Fraser IS, Hickey M. Endometrial expression of steroid receptors in postmenopausal hormone replacement therapy users: relationship to bleeding patterns. J Fam Plann Reprod Health Care. 2008;34:27–34
  19. Bamberger AM, Milde-Langosch K, Loning T, Bamberger CM. The glucocorticoid receptor is specifically expressed in the stromal compartment of the human endometrium. J Clin Endocrinol Metab. 2001;86:5071–5074
  20. Narvekar N, Critchley HO, Cheng L, Baird DT. Mifepristone-induced amenorrhoea is associated with an increase in microvessel density and glucocorticoid receptor and a decrease in stromal vascular endothelial growth factor. Hum Reprod. 2006;21:2312–2318
  21. Liang T, Hoyer S, Yu R, et al. Immunocytochemical localization of androgen receptors in human skin using monoclonal antibodies against the androgen receptor. J Invest Dermatol. 1993;100:663–666
  22. Brache V, Alvarez-Sanchez F, Faundes A, Tejada AS, Cochon L. Ovarian endocrine function through five years of continuous treatment with NORPLANT subdermal contraceptive implants. Contraception. 1990;41:169–177
  23. Ganong WF. Physiology of reproduction in women. In:  DeCherney AH, et al. editor. Current Diagnosis & Treatment Obstetrics & Gynecology. New York: Lange Medical Books/McGraw-Hill; 2007;p. 126–148
  24. Lahteenmaki P, Rauramo I, Backman T. The levonorgestrel intrauterine system in contraception. Steroids. 2000;65:693–697
  25. Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD. Clin Endocrinol (Oxf). 1982;17:529–536
  26. Reed JC, Jurgensmeier JM, Matsuyama S. Bcl-2 family proteins and mitochondria. Biochim Biophys Acta. 1998;1366:127–137
  27. Rogers PA, Lederman F, Plunkett D, Affandi B. Bcl-2, Fas and caspase 3 expression in endometrium from levonorgestrel implant users with and without breakthrough bleeding. Hum Reprod. 2000;15(Suppl 3):152–161
  28. Lockwood CJ, Runic R, Wan L, Krikun G, Demopolous R, Schatz F. The role of tissue factor in regulating endometrial haemostasis: implications for progestin-only contraception. Hum Reprod. 2000;15(Suppl 3):144–151
  29. Hiroi M, Stanczyk FZ, Goebelsmann U, Brenner PF, Lumkin ME, Mishell DR. Radioimmunoassay of serum medroxyprogesterone acetate (Provera) in women following oral and intravaginal administration. Steroids. 1975;26:373–386
  30. Ortiz A, Hirol M, Stanczyk FZ, Goebelsmann U, Mishell DR. Serum medroxyprogesterone acetate (MPA) concentrations and ovarian function following intramuscular injection of depo-MPA. J Clin Endocrinol Metab. 1977;44:32–38
  31. Pfizer . Depo-Provera Physicians' Information. [cited 2008 02/18/2008]; Available from: http://www.pfizer.com/files/products/uspi_depo_provera_contraceptive.pdf2008;
  32. Simoncini T, Mannella P, Fornari L, et al. Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells. Endocrinology. 2004;145:5745–5756
  33. Zerr-Fouineau M, Chataigneau M, Blot C, Schini-Kerth VB. Progestins overcome inhibition of platelet aggregation by endothelial cells by down-regulating endothelial NO synthase via glucocorticoid receptors. FASEB J. 2007;21:265–273
  34. Yamamoto T, Terada N, Nishizawa Y, Petrow V. Angiostatic activities of medroxyprogesterone acetate and its analogues. Int J Cancer. 1994;56:393–399
  35. Ozdemir F, Ovali E, Aydin F, et al. The in-vitro effects of medroxyprogesterone acetate on acidic pH induced apoptosis of peripheral blood mononuclear cells. J Exp Clin Cancer Res. 2004;23:93–95
  36. Aydin F, Ozdemir F, Kavgaci H, Yilmaz M, Karti S. The effects of medroxyprogesterone acetate on apoptosis of CD34+ cells. Chemotherapy. 2003;49:66–70
  37. Abe M, Yamashita J, Ogawa M. Medroxyprogesterone acetate inhibits human pancreatic carcinoma cell growth by inducing apoptosis in association with Bcl-2 phosphorylation. Cancer. 2000;88:2000–2009
  38. Akcali KC, Khan SA, Moulton BC. Effect of decidualization on the expression of Bax and Bcl-2 in the rat uterine endometrium. Endocrinology. 1996;137:3123–3131
  39. Williams TA, Verhovez A, Milan A, Veglio F, Mulatero P. Protective effect of spironolactone on endothelial cell apoptosis. Endocrinology. 2006;147:2496–2505
  40. Lovely LP, Fazleabas AT, Fritz MA, McAdams DG, Lessey BA. Prevention of endometrial apoptosis: randomized prospective comparison of human chorionic gonadotropin versus progesterone treatment in the luteal phase. J Clin Endocrinol Metab. 2005;90:2351–2356

 The research was supported in part by National Institutes of Health Grant R01 HD43175-01 and CONRAD Clinical Research Center Internal Funds.

☆☆ Conflict of interest: C.C. has nothing to disclose. S.Z. has nothing to disclose. T.D.D. has nothing to disclose. T.D.K. has nothing to disclose. D.F.A. has received research funding from Wyeth, Novo Nordisk, Bayer Healthcare, Warner Chilcott and Glaxo SmithKline; has served as a consultant to Wyeth, Bayer Healthcare, Novo Nordisk, Schering Plough, Merck, Warner Chilcott, Abbott Laboratories, and Agile Therapeutics and has received honoraria from Organon, Wyeth, Novo Nordisk and Ascend Therapeutics.

PII: S0010-7824(08)00449-6

doi: 10.1016/j.contraception.2008.08.008

Contraception
Volume 79, Issue 2 , Pages 139-145 , February 2009