Sex Hormone Levels and Risk of Breast Cancer
Breast cancer case subjects had higher BMI, younger age at menarche, and stronger family history of breast cancer than control subjects. No differences in time since menopause, reproductive history, smoking status, and alcohol use were observed between case and control subjects (Table 1).
Higher levels of total estradiol (Ptrend = .04), bioavailable estradiol (Ptrend = .03), estrone (Ptrend = .007), and estrone sulfate (Ptrend = 0.007) were statistically significantly associated with increased breast cancer risk. Compared with women in the lowest quartile, those in the highest quartiles of these hormones had a 2.4-fold to threefold higher risk for breast cancer. Progesterone, testosterone, and SHBG concentrations were not statistically significantly associated with breast cancer risk (Table 2). Analyses for total estradiol, bioavailable estradiol, and estrone were restricted to the placebo group because of statistically significant interactions of these hormones with E+P treatment.
There were no differences in baseline sex hormone levels between the placebo and treatment groups. At year 1, there was a marked increase in levels of total and bioavailable estradiol, estrone, estrone sulfate, and SHBG in the E+P group compared with the placebo group (all P < .001). The largest percentage increase was observed for estrone (median change of approximately 230%). In the placebo group, there was a modest decrease in sex hormone levels between baseline and year 1 and a slight increase in SHBG level of 3% (Table 3).
Statistically significant interactions were observed between E+P use and pretreatment levels of total estradiol (Pinteraction = .04), bioavailable estradiol (Pinteraction = .02), and estrone (Pinteraction = .02). The highest increase in breast cancer risk with combined hormone therapy was observed in women whose baseline levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles (lowest total estradiol quartile: OR for E+P vs placebo = 2.47, 95% CI = 1.28 to 4.79; lowest bioavailable estradiol quartile: OR = 2.35, 95% CI = 1.20 to 4.64; lowest estrone quartile: OR = 3.06, 95% CI = 1.52 to 6.17) (Table 4).
Women whose levels were in the second and third quartiles of these sex hormones had a non-statistically significant increased risk of breast cancer risk with E+P therapy. However, there was no evidence that E+P influenced breast cancer risk for women with total and bioavailable estradiol and estrone in the highest quartile (highest total estradiol quartile: OR for E+P vs placebo = 0.96; 95% CI = 0.44 to 2.09; Pinteraction = .04) (Table 4). Levels of estrone sulfate (Pinteraction = .93), progesterone (Pinteraction = .27), total testosterone (Pinteraction = .69), bioavailable testosterone (Pinteraction = .24), and SHBG (Pinteraction = .14) did not statistically significantly modify the effect of E+P on breast cancer risk (data not shown).
Absolute changes in sex hormone levels (total and bioavailable estradiol, estrone, estrone sulfate, and SHBG) between baseline and year 1 were not statistically significantly associated with breast cancer risk (Table 5).
Results
Baseline Characteristics of Case and Control Subjects
Breast cancer case subjects had higher BMI, younger age at menarche, and stronger family history of breast cancer than control subjects. No differences in time since menopause, reproductive history, smoking status, and alcohol use were observed between case and control subjects (Table 1).
Pretreatment Sex Hormone Levels and Breast Cancer Risk
Higher levels of total estradiol (Ptrend = .04), bioavailable estradiol (Ptrend = .03), estrone (Ptrend = .007), and estrone sulfate (Ptrend = 0.007) were statistically significantly associated with increased breast cancer risk. Compared with women in the lowest quartile, those in the highest quartiles of these hormones had a 2.4-fold to threefold higher risk for breast cancer. Progesterone, testosterone, and SHBG concentrations were not statistically significantly associated with breast cancer risk (Table 2). Analyses for total estradiol, bioavailable estradiol, and estrone were restricted to the placebo group because of statistically significant interactions of these hormones with E+P treatment.
Baseline and Year 1 Sex Hormone Levels in the Treatment and Placebo Groups
There were no differences in baseline sex hormone levels between the placebo and treatment groups. At year 1, there was a marked increase in levels of total and bioavailable estradiol, estrone, estrone sulfate, and SHBG in the E+P group compared with the placebo group (all P < .001). The largest percentage increase was observed for estrone (median change of approximately 230%). In the placebo group, there was a modest decrease in sex hormone levels between baseline and year 1 and a slight increase in SHBG level of 3% (Table 3).
Pretreatment Sex Hormone Levels and Effect of E+P Therapy on Breast Cancer Risk
Statistically significant interactions were observed between E+P use and pretreatment levels of total estradiol (Pinteraction = .04), bioavailable estradiol (Pinteraction = .02), and estrone (Pinteraction = .02). The highest increase in breast cancer risk with combined hormone therapy was observed in women whose baseline levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles (lowest total estradiol quartile: OR for E+P vs placebo = 2.47, 95% CI = 1.28 to 4.79; lowest bioavailable estradiol quartile: OR = 2.35, 95% CI = 1.20 to 4.64; lowest estrone quartile: OR = 3.06, 95% CI = 1.52 to 6.17) (Table 4).
Women whose levels were in the second and third quartiles of these sex hormones had a non-statistically significant increased risk of breast cancer risk with E+P therapy. However, there was no evidence that E+P influenced breast cancer risk for women with total and bioavailable estradiol and estrone in the highest quartile (highest total estradiol quartile: OR for E+P vs placebo = 0.96; 95% CI = 0.44 to 2.09; Pinteraction = .04) (Table 4). Levels of estrone sulfate (Pinteraction = .93), progesterone (Pinteraction = .27), total testosterone (Pinteraction = .69), bioavailable testosterone (Pinteraction = .24), and SHBG (Pinteraction = .14) did not statistically significantly modify the effect of E+P on breast cancer risk (data not shown).
Baseline to Year 1 Absolute Change in Sex Hormone Levels and Breast Cancer Risk
Absolute changes in sex hormone levels (total and bioavailable estradiol, estrone, estrone sulfate, and SHBG) between baseline and year 1 were not statistically significantly associated with breast cancer risk (Table 5).
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