Lower Pretreatment Estrogen Levels Linked to Greater Relative Breast Cancer Risk in Menopausal Women Taking Combined Hormone Therapy

Introduction: While it is known that use of estrogen plus progestin therapy is associated with an increased risk for breast cancer, the effects of pretreatment sex hormone levels on this risk were previously unknown.

Methods: The authors conducted a nested case-control study within the Women's Health Initiative (WHI), which included 16,608 postmenopausal women (age 50 to 79 years) who were randomized to 0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate, or to placebo. Women who had undergone a hysterectomy or had a history of breast cancer were excluded from the trial. Mammograms taken at baseline were negative, and WHI enrollment required 2 years of normal mammograms. Over a mean follow-up of 5.6 years, 348 women developed breast cancer, and were included in the analysis. They were matched to 348 control subjects by age at screening, race/ethnicity, and date of randomization.

Results: In the placebo group, the breast cancer risk was significantly associated with greater pretreatment levels of total estradiol, (Ptrend =0.04), bioavailable estradiol (Ptrend =0.03), estrone (Ptrend =0.007), and estrone sulfate (Ptrend =0.007; Table). Women in the highest quartiles of these hormones at baseline had a 2.4-fold to 3-fold increased risk for breast cancer compared to women in the lowest quartile.

In the estrogen plus progestin group, the effect of treatment (ie, increased risk of breast cancer) was strongest among women in the lowest quartiles for total estradiol, bioavailable estradiol, and estrone (Table). For example, the odds ratio for breast cancer was 2.47 among women in the lowest estradiol quartile compared with 0.96 among women in the highest estradiol quartile.

Absolute changes in sex hormone levels after 1 year of hormone therapy were not significantly associated with the risk for breast cancer. Hormone treatment had little or no effect on the risk for breast cancer among women in the highest quartiles for total estradiol, bioavailable estradiol, and estrogen at baseline.

Conclusion: Women with the lowest levels of total estradiol, bioavailable estradiol, and estrone before taking hormone therapy had the greatest increase in breast cancer risk during estrogen plus progestin treatment.

Table. Risk for Breast Cancer by Baseline Hormone Level Among Women Randomized to Estrogen Plus Progesterone or Placebo

E+P, estrogen plus progesterone
P value for interaction between hormone therapy and sex hormone level (continuous scale).
Data extracted from Farhat et al.


Farhat GN, Parimi N, Chlebowski RT, et al. Sex hormone levels and risk of breast cancer with estrogen plus progestin. J Natl Cancer Inst. 2013;105(19):1496-1503.

Commentary by Tamara L Wexler MD, PhD

Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in reproductive and neuroendocrinology, and an Attending in Medicine, Massachusetts General Hospital, Boston, MA.

There is little debate on the association between postmenopausal combined hormone therapy (HT; E+P) and an increase in breast cancer incidence. It was in part the increased risk in invasive breast cancer (along with coronary heart disease, stroke, and pulmonary embolism) seen with postmenopausal combined hormone therapy (E+P) that led to the early termination of the WHI randomized trial.1 Unopposed estrogen—used only in women without uteri—was not shown to have that same risk. Farhat and colleagues set out to examine whether pretreatment hormone levels impact this increase in risk.

The study was nested within the WHI. Exclusion criteria for analysis included missing serum hormone levels as well as subjects with very elevated levels (considered to be outliers).

The analysis found that endogenous estrogen levels (total and bioavailable estradiol; estrone and estrone sulfate) in the lowest quartile were statistically significantly associated with increased risk of breast cancer; testosterone level was not associated with increased breast cancer risk. In women taking hormone replacement therapy, the risk for women with lowest quartile pretreatment levels increased to that of women with highest quartile pretreatment levels.

Breast cancer also was associated with slightly higher body mass index (BMI 29.3 vs 28.5; P=0.02), family history of breast cancer, and earlier menarche.

The study design itself carries some limitations. As an observational study, there is no indication of causality. Breast cancer outcomes were obtained by screening questionnaire followed by medical record review. There was no distinction made between estrogen receptor (ER)-positive and ER-negative breast cancers, and survival was not studied. Most significantly, some of the non-HRT group likely had a history of hormone therapy use, as the WHI required only a 3-month washout of any HT,2 prior to randomization.

The results suggest that, in women who have high pretreatment estrogen levels, use of postmenopausal combined hormone therapy may not be associated with the same additional risk seen in women with lower pretreatment levels. While this may suggest that risk is conferred by a greater change in hormone levels after treatment begins, serum level changes measured after 1 year of HT (compared to baseline levels) were not associated with increased risk. It may well be that the risk is already higher in those women; the lead authors previously demonstrated an association between high endogenous estradiol (and testosterone) levels and ER-positive breast cancer, based on WHI data,3 though those findings are not consistent across all studies.

In summary, the results of the study are consistent with the authors' hypothesis that women with lower endogenous sex hormone levels and a lower baseline risk of breast cancer (versus women with higher endogenous levels), have a relatively greater increase in breast cancer incidence on combined HRT.

Whether higher endogenous hormone levels can be used to predict the relative safety of postmenopausal HT—particularly given the suggestion that that very group already has a higher risk of ER-positive breast cancer—is unclear. In addition, the predictive value of endogenous estrogen levels on other risks associated with HT has not been evaluated.


1. Rossouw JE, Anderson GL, Prentice RL, et al. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin for healthy postmenopausal women. JAMA. 2002;288:321-333.

2. Hays J, Hunt JR, Hubbell FA, et al. The Women's Health Initiative recruitment methods and results. Ann Epidemiol. 2003 Oct;13(9 Suppl):S18-77.

3. Farhat GN, Cummings SR, Chlebowski RT, et al. Sex hormone levels and risks of estrogen receptor-negative and estrogen receptor-positive breast cancers. J Natl Cancer Inst. 2011;103(7):562-570.