Comparison of the Proliferative Effects of Ethinylestradiol on Human Breast Cancer Cells in an Intermittent and a Continuous Dosing Regime

 

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Abstract

Many women would prefer fewer bleeding episodes while taking oral contraceptives. For this reason and with the intention of reducing menstruation-associated symptoms, an extended-cycle contraceptive is considered in the present paper. However, it remains unknown whether this long-term treatment is associated with a different breast cancer risk from that of the usual treatment. Therefore, in the present in vitro work we intend to compare the effect of these different treatment regimens on breast cancer risk. MCF-7 cells (human estrogen- and progesterone-receptor-positive metastatic breast cancer cells) and HCC1500 cells (human estrogen- and progesterone-receptor-positive primary breast cancer cells) were incubated with physiological concentrations of ethinylestradiol (EE). Usual and extended cycles were mimicked by incubation periods of 18 hours with EE followed by 6 hours without EE and 24 hours with EE for 3 days, respectively. In both cell lines, EE elicited a significant increase in the proliferation rate. No significant difference was found between the two incubation periods. Our results indicate that continuously administered ethinylestradiol may not increase breast cancer risk in comparison to intermittent application. However, clinical studies are necessary to prove these in vitro results.

References

• 1 Russo IH, Russo J. The role of estrogen in breast cancer. In: Russo J, Russo IH (eds.) Molecular Basis of Breast Cancer Prevention Treatment. Heidelberg: Springer Verlag 2005: 89-136
  Google Scholar
• 2 Fowke JH, Shu XO, Dai Q, Jin F, Cai Q, Gao YT. et al . Oral contraceptive use and breast cancer risk: modification by NAD(P)H:quinone oxoreductase (NQO1) genetic polymorphisms.  Cancer Epidemiol Biomarkers Prev. 2004;  13 1308-1315
  PubMedGoogle Scholar
• 3 Collaborative Group on Hormonal Factors in Breast Cancer . Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies.  Lancet. 1996;  347 1713-1727
  CrossrefPubMedGoogle Scholar
• 4 Althuis MD, Brogan DR, Coates RJ, Daling JR, Gammon MD, Malone KE. et al . Hormonal content and potency of oral contraceptives and breast cancer risk among young women.  Br J Cancer. 2003;  88 50-57
  CrossrefPubMedGoogle Scholar
• 5 Kahlenborn C, Moduqno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis.  Mayo Clinic Proc. 2006;  81 1290-1302
  PubMedGoogle Scholar
• 6 Den Tonkelaar I, Oddens BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use.  Contraception. 1999;  59 357-362
  CrossrefPubMedGoogle Scholar
• 7 Sillem M, Schneidereit R, Heithecker R, Mueck AO. Use of an oral contraceptive containing drospirenone in an extended regimen.  Eur J Contraception Reprod Health Care. 2004;  8 162-169
  PubMedGoogle Scholar
• 8 Sulak PJ, Cressman BE, Waldrop E, Holleman S, Kuehl TJ. Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms.  Obstet Gynecol. 1997;  89 179-183
  CrossrefPubMedGoogle Scholar
• 9 Wiegratz I, Kuhl H. Long-cycle treatment with oral contraceptives.  Drugs. 2004;  64 2447-2462
  CrossrefPubMedGoogle Scholar
• 10 Schoonen WG, Joosten JW, Kloosterboer HJ. Effects of two classes of progestagens, pregnane and 19-nortestosterone derivatives, on cell growth of human breast tumor cells: I. MCF-7 cell lines.  J Steroid Biochem Mol Biol. 1995;  55 423-437
  CrossrefPubMedGoogle Scholar
• 11 Humpel M, Tuber U, Kuhnz W, Pfeffer M, Brill K, Heithecker R. et al . Comparison of serum ethinyl estradiol, sex-hormone-binding globulin, corticoid-binding globulin and cortisol levels in women using two low-dose combined oral contraceptives.  Horm Res. 1990;  33 35-39
  PubMedGoogle Scholar
• 12 Jeng MH, Parker CJ, Jordan VC. Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation.  Cancer Res. 1992;  52 6539-6546
  PubMedGoogle Scholar
• 13 Kloosterboer HJ, Schoonen WG, Deckers GH, Klijn JG. Effects of progestagens and Org OD14 in in vitro and in vivo tumor models.  J Steroid Biochem Mol Biol. 1994;  49 311-318
  PubMedGoogle Scholar
• 14 Mueck AO, Seeger H, Wallwiener D. Comparison of the proliferative effects of estradiol and conjugated equine estrogens on human breast cancer cells and impact of continuous combined progestogen addition.  Climacteric. 2003;  6 221-227
  CrossrefPubMedGoogle Scholar
• 15 Krämer EA, Seeger H, Krämer B, Wallwiener D, Mueck AO. The effects of progesterone, medroxyprogesterone acetate, and norethisterone on growth factor- and estradiol-treated human cancerous and noncancerous breast cells.  Menopause. 2005;  12 468-474
  CrossrefPubMedGoogle Scholar
• 16 Guengerich FP. Metabolism of 17 alpha-ethinylestradiol in humans.  Life Sci. 1990;  47 1981-1988
  CrossrefPubMedGoogle Scholar
• 17 Fortunati N, Catalano MG. Sex hormone-binding globulin (SHBG) and estradiol cross-talk in breast cancer cells.  Horm Metab Res. 2006;  38 236-240
  Article in Thieme ConnectPubMedGoogle Scholar
• 18 Timmer CJ, Apter D, Voortman G. Pharmacokinetics of 3-keto-desogestrel and ethinylestradiol released from different types of contraceptive vaginal rings.  Contraception. 1990;  42 629-642
  CrossrefPubMedGoogle Scholar
• 19 Lippert C, Seeger H, Wallwiener D, Mueck AO. Comparison of the effects of 17alpha-ethinylestradiol and 17beta-estradiol on the proliferation of human breast cancer cells and human umbilical vein endothelial cells.  Clin Exp Obstet Gynecol. 2002;  29 87-90
  PubMedGoogle Scholar
• 20 Lippert C, Seeger H, Wallwiener D, Mueck AO. Comparison of the effects of continuous combined and sequential combined medroxyprogesterone acetate-estradiol treatment on the proliferation of MCF-7 cells.  Climacteric. 2000;  3 271-277
  CrossrefPubMedGoogle Scholar
• 21 Lippert C, Seeger H, Wallwiener D, Mueck AO. The effect of medroxyprogesterone acetate and norethisterone on the estradiol stimulated proliferation in MCF-7 cells: comparison of continuous combined versus sequential combined estradiol/progestin treatment.  Eur J Gynaecol Oncol. 2001;  22 331-335
  PubMedGoogle Scholar
• 22 Seeger H, Wallwiener D, Mueck AO. The effect of progesterone and synthetic progestins on serum- and estradiol-stimulated proliferation of human breast cancer cells.  Horm Metab Res. 2003;  35 76-80
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Catherino WH, Jeng MH, Jordan VC. Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism.  Br J Cancer. 1993;  67 945-952
  PubMedGoogle Scholar

Correspondence

Dr. G.S. Merki-Feld

Clinic of Reproductive Endocrinology

Department of Gynecology and Obstetrics

University Hospital

Frauenklinikstr. 10

8091 Zurich

Switzerland

Phone: +41/1/255 50 09

Fax: +41/1/255 43 76

Email: gabriele.merki@usz.ch