Breast cell proliferation in postmenopausal women during HRT evaluated through fine needle aspiration cytology

Breast Cancer Res Treat. 2003 Mar;78(2):159-65. doi: 10.1023/a:1022987618445.


The basis of breast cancer risk associated with hormonal therapies may lie in the regulation of cell proliferation. In a prospective, double-blind, randomized study postmenopausal women were given continuous combined hormone replacement therapy (HRT) either as estradiol valerate 2 mg/dienogest 2 mg, (E2V/DNG) or estradiol 2 mg/noretisterone acetate 1 mg (E2/NETA) for 6 months. Fine needle aspiration (FNA) biopsies were used for immunocytochemical analysis of breast cell proliferation before and during treatment. From 45 women completing the study 135 biopsies were obtained. In the total material there was a more than 4-fold increase in proliferation between baseline and 3 months (p < 0.001). The mean percentage of MIB-1 positive breast cells increased from 2.2 to 9.1%. In some individual women values were as high as 25%. No further increase was recorded at 6 months. While numerical values were somewhat lower in the E2V/DNG group, there were no significant differences between treatments. There was a positive correlation between breast cell proliferation (MIB-1%) and circulating levels of both estradiol (r(s) = 0.54, p < 0.01) and estrone (r(s) = 0.53, p < 0.01) after 3 and 6 months of treatment. No correlations with other endogenous hormones, proteins or with the two exogenous progestogens dienogest and norethisterone were observed. Increased breast cell proliferation should probably be regarded as an unwanted side-effect during HRT. Means to identify those women with the most pronounced proliferative response should be developed. The FNA biopsy technique may be a useful tool to monitor and evaluate the proliferative response to HRT in the normal breasts of postmenopausal women.

Publication types

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

MeSH terms

  • Biopsy, Needle / methods
  • Breast / chemistry
  • Breast / drug effects*
  • Breast / pathology*
  • Cell Division / drug effects*
  • Double-Blind Method
  • Drug Combinations
  • Estradiol / analogs & derivatives
  • Estradiol / blood
  • Estradiol / pharmacology*
  • Estriol / pharmacology*
  • Estrogen Replacement Therapy / adverse effects*
  • Estrone / blood
  • Female
  • Humans
  • Ki-67 Antigen / analysis
  • Middle Aged
  • Nandrolone / analogs & derivatives
  • Nandrolone / pharmacology*
  • Norethindrone / analogs & derivatives*
  • Norethindrone / pharmacology*
  • Postmenopause
  • Prospective Studies


  • Drug Combinations
  • Ki-67 Antigen
  • estradiol valerate-dienogest
  • Estrone
  • Estradiol
  • Trisequens
  • Nandrolone
  • Estriol
  • Norethindrone