Journal Scan article by Ken Blank and John Chang

Reviewers: Ken Blank, MD and John Chang, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: February 7, 2002

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Grodstein, F, Stampfer, MJ, Colditz, GA, Et al.
The New England Journal of Medicine
June 19 1997 Vol. 336 No.25

The risks and benefits of prescribing estrogen with or without progestins to postmenopausal women have been debated for many years. The known benefits of postmenopausal hormone replacement therapy (PMHRT) includea decrease in the incidence of coronary artery disease (CAD) and osteoporosis. These benefits must be weighed against the risks, the most concerning of which is a possible increase in the risk of cancer. A large trial reported in The New England Journal of Medicine (NEJM) helps clarify the controversy.

The Nurses' Health Study began in 1976 when over 120,000 registered nurses completed questionnaires concerning their medical history, including information on menopause, cardiovascular disease and cancer. After twenty years of diligent follow-up, the results were reported in the June 19, 1997 issue of NEJM. The major finding was that women who take hormones have a lower mortality compared to a control group that never used hormones. The drop in mortality rate was largely due to a decrease in death from CAD.

These positive effects were lost if the hormones were discontinued: women off hormones greater than 5 years had no benefit from past use, and may be at slightly higher risk for death from all causes compared to the control group.Critics of the study point out that the reduced mortality from cancer may be due to earlier detection of cancer among hormone users, marked lifestyle differences between users and non- users, and not the hormones, that may account for lower mortality from CAD. Nevertheless, this large study conducted over 3 decades will certainly influence patient and physician choices.

A critical issue specifically addressed in this study was association of PMHRT and breast cancer. Prior reports have shown conflicting results regarding this association: Some have shown PMHRT to increase the risk of breast cancer while others found the opposite- that PMHRT decreases the risk of breast cancer. The current study found hormone therapy clearly reduced the risk of breast cancer in current users taking the hormones less than 10 years. However, women who stay on hormones greater than 10 years had a significantly increased risk of breast cancer compared to non-users. It is unclear why short term usage of PMHRT should protect against breast cancer,

while usage over 10 years increases this risk. However, it is important to recognize that there remained an overall survival advantage to continuing hormone replacement longer than 10 years because the increased risk of breast cancer did not completely offset the continued cardioprotective effect of long term usage.

Another major issue addressed by this study was whether a positive family history of breast cancer should be a contraindication to PMHRT. The data showed that patients with a positive family history, defined as a mother or sister with breast cancer, did not have any greater risk than those with no family history when taking PMHRT.

Endometrial (uterine) cancer has also been associated with PMHRT. A study published in 1996 found that the addition of progestins to estrogen helped reduce this risk. However, several small studies have suggested that the addition of progestins may diminish the cardioprotective effects of estrogen, and that combined therapy (estrogen and progestins) may increase the risk of breast cancer. This study found that that combined therapy users had a reduction in coronary artery disease equal to and maybe greater than women on estrogen alone. Information on the relative risk of dying from breast and endometrial cancer in women on combined therapy was not provided.

The critical questions faced by postmenopausal women include, "should I start PMHRT? And, if so, when and for how long?" These questions need be discussed with your family physician and the answers will surely be tailored to each individual. However, the results from the Nurses' Health Study clearly indicate a benefit to PMHRT in the lowering the risk of death from both CAD and cancer. The only caveat being women who take PMHRT greater than 10 years are at increased risk of breast cancer which is offset by a continued cardioprotective effect.



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