Effect of combined oral contraceptives on breast epithelial proliferation in young women

Breast J. Sep-Oct 2008;14(5):450-5. doi: 10.1111/j.1524-4741.2008.00621.x. Epub 2008 Jul 24.


The mammary gland undergoes morphologic changes during the menstrual cycle. Proliferation of normal breast epithelium is most extensive during the natural luteal phase. To determine the impact of one cycle of a combined oral contraceptive (COC) on breast homeostasis, we evaluated the proliferation index (PI), determined by KI-67 expression, in normal human mammary epithelial cells and correlated it with cellular proliferation in spontaneous menstrual cycles during the same period. Normal breast tissue samples were obtained from 82 patients randomized in two groups. Forty-two women in group A received one cycle of a COC (30 mug ethinyl estradiol and 150 mug levonorgestrel) administrated daily for 21 days, beginning on the first day of the menstrual cycle. Group B patients (n = 40) experienced a natural menstrual cycle. Menstrual cycle phase characterization was based on the date of the last period and subsequent menses and on progesterone serum levels obtained at the time of biopsy. The PI (number of Ki-67-positive nuclei per 1,000 epithelial cells), was significantly larger in group A (5.47 +/- 3.87), than in group B (3.27 +/- 3.24), p < 0.01. A cyclical variation of PI was observed in COC cycles. The rise in PI in the first week of the COC cycles was significantly higher than in the natural cycle (COC = 7.02 +/- 4.94; non-COC = 1.10 +/- 0.67; p < 0.0011). There was no significant difference between the two groups during the other weeks. Additionally, there was an inverse correlation between proliferation and chronological age, irrespective of the stage of the cycle. The PI of COC (p = 0.175) and natural cycles (p = 0.466) were not statistically different in younger patients. COC users have increased proliferative activity at the beginning of the menstrual cycle. This alteration in the pattern of proliferative activity may relate to the increased risk of breast cancer that has been associated with COCs.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Biopsy, Needle
  • Breast / drug effects
  • Breast / pathology*
  • Cell Proliferation / drug effects*
  • Contraceptives, Oral, Combined / administration & dosage*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Female
  • Humans
  • Immunohistochemistry
  • Linear Models
  • Luteal Phase / drug effects
  • Luteal Phase / physiology
  • Menstrual Cycle / drug effects*
  • Menstrual Cycle / physiology
  • Probability
  • Progesterone / metabolism
  • Radioimmunoassay
  • Reference Values
  • Sensitivity and Specificity


  • Contraceptives, Oral, Combined
  • Progesterone