Histologic changes in the breast with menopausal hormone therapy use: correlation with breast density, estrogen receptor, progesterone receptor, and proliferation indices

Menopause. Jan-Feb 2008;15(1):67-73. doi: 10.1097/gme.0b013e318054e29a.


Objective: This retrospective study systematically compared mammographic density with histology in women receiving or not receiving menopausal hormone therapy (HT).

Design: This study was approved by the institutional review board. Twenty-eight postmenopausal women using HT were matched with 28 postmenopausal women not using HT at the time of breast cancer diagnosis. Noncancerous tissue from mastectomy specimens was examined histologically to quantitate the content of fibrous stroma, ducts, and lobule types 1, 2, and 3. Tissue samples were also evaluated for estrogen receptor, progesterone receptor, and Ki67 activity in the ducts and lobules. Breast density was quantified by digitizing the contralateral mammogram and computer-assisted interactive thresholding.

Results: High breast density in women using HT was correlated with greater fibrous stroma (P = 0.020) and lobule type 1 (P = 0.016). Breast density also correlated with Ki67 activity in the ducts (P = 0.031) and lobules (P= 0.023) for both groups combined. Estrogen and progesterone receptors did not correlate with either breast density or HT use.

Conclusions: Increased fibrous stroma and lobule type 1 are associated with increasing mammographic density in women using HT, independent of estrogen and progesterone receptor up-regulation. These findings suggest that increased breast density may be mediated through a paracrine effect. The increase in breast cancer risk with HT use may be due to an increase in target lobule type 1 cells.

MeSH terms

  • Breast / drug effects*
  • Breast / pathology*
  • Breast Neoplasms / etiology
  • Breast Neoplasms / pathology
  • Case-Control Studies
  • Estrogen Receptor alpha / drug effects
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Replacement Therapy / adverse effects*
  • Estrogen Replacement Therapy / methods
  • Female
  • Humans
  • Image Interpretation, Computer-Assisted
  • Ki-67 Antigen / analysis
  • Mammography
  • Middle Aged
  • Postmenopause
  • Receptors, Progesterone / drug effects
  • Receptors, Progesterone / metabolism*


  • Estrogen Receptor alpha
  • Ki-67 Antigen
  • Receptors, Progesterone