[Skip to Content]
[Skip to Content Landing]
Citations 0
August 9, 2000

Estrogen-Progestin Replacement and Risk of Breast Cancer

Author Affiliations

Stephen J.LurieMD, PhD, Contributing EditorIndividualAuthorPhil B.FontanarosaMD, Executive Deputy EditorIndividualAuthor

JAMA. 2000;284(6):691-694. doi:10.1001/jama.284.6.691

To the Editor: Dr Schairer and colleagues1 reported an increase in RR of breast cancer with the use of estrogen-progestin therapy compared with estrogen use alone. This increase in RR associated with progestin use may be reflected in the mammographic density changes seen with HRT.

Breast density increases in many women undergoing HRT. Among women undergoing continuous estrogen-progestin therapy, 27% had an increase in breast density, compared with 10% of those using cyclic combined therapy, and only 5% of women using estradiol alone.2 Likewise, in premenopausal women, the breasts are more radiographically dense during the luteal phase than the follicular phase of the menstrual cycle3 when progesterone levels are highest. Conversely, use of tamoxifen citrate, which decreases breast cancer risk, is associated with a decrease in mammographic density.4

Studies using quantitative methods of assessing mammographic breast density have shown an increased risk of breast cancer for women with a higher percentage of the breast occupied by dense tissue.5 High-risk histology, such as atypical hyperplasia and lobular carcinoma in situ, is more commonly seen in women with high-density mammograms,5 thus supporting the hypothesis that increased breast density is associated with an increase in breast cancer risk. Likewise, benign breast biopsy results from women using estrogen plus progestin have significantly higher proliferation indices compared with those from women using estrogen alone or those not receiving HRT.6 In addition, the proliferation noted in women using estrogen with progestin in this study was localized to the terminal duct-lobular unit, which is the site of development of most breast cancers.6

Since mammographically dense breasts are associated with an increase in breast cancer risk, women who have an increase in mammographic density in response to HRT may be at higher risk for developing breast cancer than those women who do not experience a change in density. Unlike most breast cancer risk factors, breast density can be influenced. Decreasing breast density also may decrease breast cancer risk, and further studies of this possible association may be helpful.

Schairer  CLubin  JTroisi  RSturgeon  SBrinton  LHoover  R Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.  JAMA. 2000;283:485-491.Google Scholar
Persson  IThurfjell  EHolmberg  L Effect of estrogen and estrogen-progestin replacement regimens on mammographic breast parenchymal density.  J Clin Oncol. 1997;15:3201-3207.Google Scholar
White  EVelentagas  PMandelson  MT  et al.  Variation in mammographic breast density by time in menstrual cycle among women aged 40-49 years.  J Natl Cancer Inst. 1998;90:906-910.Google Scholar
Son  HJOh  KK Significance of follow-up mammography in estimating the effect of tamoxifen in breast cancer patients who have undergone surgery.  AJR Am J Roentgenol. 1999;173:905-909.Google Scholar
Boyd  NFByng  JWJong  RA Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study.  J Natl Cancer Inst. 1995;87:670-675.Google Scholar
Hofseth  LJRaafat  AMOsuch  JRPathak  DRSlomski  CAHaslam  SZ Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast.  J Clin Endocrinol Metab. 1999;84:4559-4565.Google Scholar