Skip to main content
SpringerLink
Log in

Effects of Oral Contraceptives on Breast Epithelial Proliferation

  • Conference Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The association between oral contraceptive (OC) use and breast cancer is not fully understood. Estrogen is a known mitogen to breast epithelial cells, but there is still a controversy about the effect of added progestogens. Fine needle aspiration (FNA) biopsies were used to assess epithelial proliferation in normal breast tissue from 106 healthy premenopausal women with and without oral contraceptives. In 26 women biopsies were performed before and after 2 months of OC use. Proliferation, expressed as percentage of Ki-67/MIB-1 positive cells, was correlated to endogenous progesterone, androgenic/anabolic compounds and exogenous progestogen. We found a higher proliferation (p=0.03) in OC users compared to non users, with mean values of 4.8 and 2.2, respectively. There was a positive correlation between proliferation and progesterone levels in non-users and with serum levonorgestrel concentrations in women using OCs containing this progestogen (rs=0.43, p=0.02). Women using OCs had significantly lower serum androgen levels compared to naturally cycling women and free testosterone levels displayed an inverse relation to breast epithelial proliferation. There was a marked variation in the response to exogenous sex steroids. In certain women after 2 months of OC use, the percentage of MIB-1 positive cells was as high as 40–50%. The results add to the growing evidence that progestogens may be mitogenic in breast tissue. Increased proliferation during hormonal contraception should be regarded as an unwanted and potentially hazardous side effect. Efforts should be made to define hormonal contraceptive regimens which minimize breast epithelial proliferation and to identify those women with the most pronounced proliferative response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. 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 347: 1713-1727, 1996

    Google Scholar 

  2. Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE: Increased cell division as a cause of human cancer. Cancer Res 50: 7415-7421, 1990

    Google Scholar 

  3. Key TJ, Pike MC: The dose-effect relationship between ‘unopposed’ estrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer 57: 205-212, 1988

    Google Scholar 

  4. Gompel A, Malet C, Spritzer P, Lalardrie JP, Kuttenn F, Mauvais-Jarvis P: Progestin effect on cell proliferation and 17-b-hydroxysteroid dehydrogenase activity in normal human breast cells in culture. J Clin Endocrinol Metab 63: 1174-1180, 1986

    Google Scholar 

  5. Longacre TA, Bartow SA: A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am J Surg Pathol 10: 382-393, 1986

    Google Scholar 

  6. Söderqvist G, Isaksson E, von Schoultz B, Carlström K, Tani E, Skoog L: Proliferation of breast epithelial cells in healthy women during the menstrual cycle. Am J Obstet Gynecol 176: 123-128, 1997

    Google Scholar 

  7. Williams G, Anderson E, Howell A, Watson R, Coyne J, Roberts SA, Potten CS: Oral contraceptive (OCP) use increases proliferation and decreases oestrogen receptor content of epithelial cells in the normal human breast. Int J Cancer 48: 206-210, 1991

    Google Scholar 

  8. Anderson TJ, Battersby S, King RJ, McPherson K, Going JJ: Oral contraceptive use influences resting breast proliferation. Hum Pathol 20: 1139-1144, 1989

    Google Scholar 

  9. Franzén S, Zajicek J: Aspiration biopsy in diagnosis of palpable lesions of the breast. Critical review of 3479 consecutive biopsies. Acta Radiol Ther Phy Biol 7(4): 241-262, 1968

    Google Scholar 

  10. Costa MJ, Tadros T, Hilton G, Birdsong G: Breast fine needle aspiration cytology. Utility as a screening tool for clinically palpable lesions. Acta Cytol 37: 461-471, 1993

    Google Scholar 

  11. Skoog L, Rutqvist LE, Wilking N: Analysis of hormone receptors and proliferation fraction in fine-needle aspirates from primary breast carcinomas during chemotherapy or tamoxifen treatment. Acta Oncol 31: 139-141, 1992

    Google Scholar 

  12. Skoog L, Humla S, Isaksson S, Tani E: Immunocytochemical analysis of receptors for estrogen and progesterone in fine needle aspirates from human breast carcinomas. Diagn Cytopathol 6: 95-98, 1990

    Google Scholar 

  13. Söderqvist G, von Schoultz B, Tani E, Skoog L: Estrogen and progesterone receptor content in breast epithelial cells from healthy women during the menstrual cycle. Am J Obstet Gynecol 168: 874-879, 1993

    Google Scholar 

  14. Gerdes J, Li L, Schlueter C, Duchrow M, Wohlenberg C, Gerlach C, Stahmer I, Kloth S, Brandt E, Flad HD: Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol 138: 867-873, 1991

    Google Scholar 

  15. Brody S, Carlström K, Lagrelius A, Lunell N-O, Rosenborg L: Serum levels of 4-androstene-3,17-dione in menstruating and postmenopausal women. Evaluation of a radioimmunoassay and correlation to bone mineral content and endometrial pathology. Acta Obstet Gynecol Scand 62: 531-534, 1983

    Google Scholar 

  16. Stege R, Eriksson A, Henriksson P, Carlström K: Orchidectomy or estrogen treatment in prostatic cancer: Effects on serum levels of adrenal androgens and related steroids. Int J Androl 10: 581-587, 1987

    Google Scholar 

  17. Södergård R, Bäckström T, Shanbag V, Carstensen H: Calculation of free and bound fractions of testosterone and estradiol-17b to plasma proteins at body temperature. J Steroid Biochem 18: 801-804, 1982

    Google Scholar 

  18. Weiner E, Johansson EDB: Plasma levels of d-Norgestrel estradiol and progesterone during treatment with silastic implants containing d-Norgestrel. Contraception 14: 81-92, 1976

    Google Scholar 

  19. Olsson SE: Contraception with subdermal implants releasing levonorgestrel. A clinical and Pharmological study. Acta Obstet Gynecol Scand Suppl 142, 1987

  20. Peterson OW, Hoyer PE, van Deurs B: Frequency and distribution of oestrogen receptor-positive cells in normal nonlactating human breast tissue. Cancer Res 47: 5748-5751, 1987

    Google Scholar 

  21. Harris JR, Lippman ME, Veronesi U, Willett W: Breast cancer (2). N Engl J Med 327: 390-398, 1992

    Google Scholar 

  22. Moore MR, Hathaway LD, Bircher JA: Progestin stimulation of thymidine kinase in the human breast cell line T47D. Biochim Biophys Acta 1096: 1174-1180, 1991

    Google Scholar 

  23. Bonney RC: The role of progestins and antiprogestins in the treatment of breast cancer. Endocrinol Rel Cancer 3: 113-125, 1996.

    Google Scholar 

  24. Miller WR, Langdon SP: Steroid hormones and cancer II. Lessons from experimental systems. Eur J Surg Oncol 23: 163-183, 1997

    Google Scholar 

  25. Vihko R, Isomaa V: Endocrine aspects of endometrial cancer. In: Voigt KD Knabbe C (eds) Endocrine Dependent Tumors. Karen Press, New York, 1989, pp 197-214

    Google Scholar 

  26. 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 92: 328-332, 2000

    Google Scholar 

  27. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R: Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 283: 485-491, 2000

    Google Scholar 

  28. Potten CS, Watson RJ, Williams GT, Tickle S, Roberts SA, Harris M: The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer 58: 163-170, 1988

    Google Scholar 

  29. Cline JM, Söderqvist G, von Schoultz E, Skoog L, von Schoultz B: Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. Am J Obstet Gynecol 174: 93-100, 1996

    Google Scholar 

  30. Isaksson E, Cline JM, Skoog L, Söderqvist G, Wilking N, von Schoultz E, von Schoultz B: p53 expression in breast and endometrium during estrogen an tamoxifen treatment of surgically postmenopausal cynomolgous macaques. Breast Cancer Res Treat 53: 61-67, 1999

    Google Scholar 

  31. Greendale GA, Reboussin BA, Sie A, Singh HR, Olson LK, Gatewood O, Bassett LW, Wasilanskas C, Bush T, Barrett-Connor E: Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Ann Intern Med 130: 262-269, 1999

    Google Scholar 

  32. Lundström E, Wilczek B, von Palffy Z, Söderqvist G, von Schoultz B: Mammographic breast density during hormone replacement therapy: Differences according to treatment. Am J Obstet Gynecol 181: 348-353, 1999

    Google Scholar 

  33. Silva PD, Gentzschein EEK, Lobo RA: Androstenedione may be a more important precursor of tissue dihydrotestosterone than testosterone in women. Fertil Steril 48: 4419-4422, 1998

    Google Scholar 

  34. Birrell SN, Bentel JM, Hickey TE, Ricciardelli C, Weger MA, Horsfall DJ, Tilley WD: Androgens induce divergent proliferative responses in human breast cell lines. J Steroid Biochem Mol Biol 52: 459-467, 1995

    Google Scholar 

  35. Pye JK, Mansel RE, Hughes LE: Clinical experience of drug treatments for mastalgia. Lancet 2: 373-377, 1985

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Oncology, Radiumhemmet, Sweden

    Erika Isaksson & Eva von Schoultz

  2. Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden

    Viveca Odlind, Gunnar Söderqvist, György Csemiczky & Bo von Schoultz

  3. Department of Obstetrics and Gynecology, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden

    Kjell Carlström

  4. Pathology and Cytology, Karolinska Hospital, Stockholm, Sweden

    Lambert Skoog

Authors
  1. Erika Isaksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eva von Schoultz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Viveca Odlind
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gunnar Söderqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. György Csemiczky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kjell Carlström
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lambert Skoog
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bo von Schoultz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Isaksson, E., Schoultz, E.v., Odlind, V. et al. Effects of Oral Contraceptives on Breast Epithelial Proliferation. Breast Cancer Res Treat 65, 163–169 (2001). https://doi.org/10.1023/A:1006482418082

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006482418082

Search

Navigation