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Delaying Hormone Use Cuts Breast Cancer Risk

By Nancy Walsh, Staff Writer, MedPage Today
Published: January 28, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Earn CME/CE credit
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Action Points  
  • Explain that women who begin using hormone therapy close to the time of menopause are at greater risk for breast cancer than those who wait five years or more.


  • Note that for women who stop hormone therapy, the risk for breast cancer falls to the level of nonusers after two years.
Women who begin using hormone therapy close to the time of menopause are at greater risk for breast cancer than those who wait five years or more, a large prospective study found.

Among current users of estrogen-only hormone formulations who began the therapy soon after menopause, the risk of breast cancer was significantly higher than in nonusers (RR 1.43, 95% CI 1.35 to 1.51, P<0.001), according to Valerie Beral, MBBS, and colleagues from the University of Oxford in England.

But for those who deferred the therapy for five years or more, the relative risk was not increased (RR 1.05, 95% CI 0.89 to 1.24, P=0.6) the researchers reported online in the Journal of the National Cancer Institute.

The risk among women currently taking estrogen-progestin formulations was greater than for those taking estrogen alone, with relative risks of 1.53 (95% CI 1.38 to 1.70, P<0.001)) and 2.04 (95% CI 1.95 to 2.14, P<0.001) among those beginning more and less than five years after menopause, respectively.

Data from the Women's Health Initiative (WHI) in the U.S. suggested that there was little risk of breast cancer associated with estrogen-only hormone therapy, but in that study most women in the estrogen arm began treatment more than five years after menopause.

To clarify whether the timing of starting treatment influences breast cancer risk, Beral and her collaborators from the Million Women Study recruited almost 1.3 million women from the U.K. between 1996 and 2001, obtaining information on sociodemographic and health factors, as well as their history of hormone use.

Participants' average age was 56.6 years at enrollment.

A total of 55% had used hormone therapy at some point, and 35% were current users.

During more than four million woman-years of follow-up, 15,759 breast cancers were diagnosed, 61% in women who had ever used hormone therapy and 45% in women currently using the hormones.

Beral and her co-investigators found increased adjusted risks for both estrogen-only and estrogen-progestin formulations in both current and past users (P for heterogeneity <0.001).

Risk remained elevated for two years after cessation of therapy (RR 1.16, 95% CI 1.08 to 1.24, P<0.001) but subsequently fell to the level seen in women who never used hormones (RR 0.99, 95% CI 0.93 to 1.05), the researchers reported.

The researchers also calculated standardized incidence rates for women on hormone therapy ages 50 to 59:

  • Never users, 0.30% per year (95% CI 0.29 to 0.31)
  • Estrogen-alone beginning less than five years after menopause, 0.43% per year (95% CI 0.42 to 0.45)
  • Estrogen-alone beginning at or after five years, 0.32% (95% CI 0.27 to 0.37)
  • Estrogen-progestin beginning less than five years after menopause, 0.61% (95% CI 0.59 to 0.64)
  • Estrogen-progestin beginning at or after five years, 0.46% (95% CI 0.41 to 0.51)

Greater risks also were seen for estrogen receptor-positive tumors in estrogen-alone users (RR 1.76, 95% CI 1.59 to 1.94, P for heterogeneity =0.005) and in estrogen-progestin users (RR 3.10, 95% CI 2.86 to 3.36, P for heterogeneity <0.001).

When the researchers looked at potential confounders, they found that incidence rates among women who never used hormone therapy increased with greater body mass index, but rates among users were not affected by body mass index.

Adjustment for other factors such as having a first-degree relative with breast cancer and age at menarche did not affect the results.

In discussing their findings, Beral and colleagues observed, "In this large prospective study we found substantial and clinically important heterogeneity in the effects of hormonal therapy on breast cancer incidence among postmenopausal women."

A limitation of their study was possible residual misclassification, with information on hormone use being obtained about 1.4 years before the detection of breast cancers, which could slightly attenuate relative risk estimates.

In an accompanying editorial, Rowan T. Chlebowski, MD, PhD, of Harbor-UCLA Medical Center in Torrance, Calif., and Garnet L. Anderson, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, compared the findings from this study with those from the WHI.

"Given the considerable methodological differences between these studies, the similarity of results is remarkable and increases confidence in the validity of the conclusions," they commented.

However, they noted that the discrepant results in the two studies regarding risk associated with estrogen-alone hormone therapy represents an unresolved question.

"Additional post-intervention follow-up of the WHI estrogen-only clinical trial currently under way should lead to further clarification of this issue," Chlebowski and Anderson wrote.

The study was funded by Cancer Research UK and the UK Medical Research Council.

All authors declared no financial conflicts of interest.



Primary source: Journal of the National Cancer Institute
Source reference:
Beral V, et al "Breast cancer risk in relation to the interval between menopause and starting hormone therapy" J Natl Cancer Inst 2011; 103: 296-305.


Additional source: Journal of the National Cancer Institute
Source reference:
Chlebowski R, Anderson G "The influence of time from menopause and mammography on hormone therapy-related breast cancer risk assessment" J Natl Cancer Inst 2011; 103: 1-2.
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Add Your Knowledge Add Your Knowledge
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Contribute your own thoughts, experience, questions, and knowledge to this story for the benefit of all MedPage Today readers.
Add Your Knowledge
Add Your Knowledge Gregory Ventana - Jan 28, 2011
Just to be clear, there was no human estrogen in the products covered by this study. It would be helpful if media sources would stop using the generic term "estrogen" when referring to hormones that may be similar to human estrogen, but that are actually hormones derived from another species of animal. Study participants used conjugated equine hormones: either "estrogen" alone (Premarin) or combined with progestin (Prempro), a synthetic variant of the natural hormone progesterone. Estrogen-like hormones derived from the urine of pregnant mares (Premarin is short for PREgnant MAre uRINe) are not human estrogens such as estradiol or estriol. They are equine hormones, with equilin being the predominant hormone along with other variations of horse estrogens. While equine estrogens are similar to human estrogens they are molecularly different. And as anyone who ever took organic chemistry should be able to tell you, a seemingly tiny difference in a molecule can translate into a significant difference in how the human body utilizes that molecule. As far as the human body is concerned, conjugated equine hormones are a foreign substance which were never meant to be ingested by people. It should not surprise anyone that women who take these hormones can experience significant short-term and long-term side effects, including an increased risk of cancer.

Add Your Knowledge R. Demczuk MD - Jan 29, 2011
Why are you still printing and why are people still studying a study where one arm used Prempro. We know unequivocally that Provera should never be used. We also know that there are better replacements (with less risk) than Premarin yet your pages constantly reprint studies that should have no funding. I may just unsubscribe because your information is frequently irrelevant. ScienceNews.com has newer, more important information. Medpage today is so out of date establishment medicine. Who are your editors? Not only is the generic class term of estrogen misused but the specific chemical term "progesterone" is frequently incorrectly used as a general term when the correct GENERAL class term is "progestogen" and the term for all not human molecular "progestogens" is "progestin" which is used correctly above. Valerie at Oxford, congratulations on landing money to statistically look yet again at a flawed study. What a waste of your time.

Add Your Knowledge varian keller - Jan 29, 2011
This study would seem to indicate that when estrogen (and not limited to Premarin)is administered orally in doses high enough to overcome the first pass on the liver and early in the menopause, it may increase breast cancer risk. The negative effects of this insult to the liver and therefore the metabolic system might explain these and many other such observations. This combined with the fact that this method of administration results in estrogen metabolites that differ in various ways from endogenous sorces, would have one conclude that some harmful effects should be expected. Offering ERT candidates transdermal formulations would eliminate the problems resulting from the oral route.

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