A 12-month reduced-calorie weight loss, with or without exercise, produced large and statistically significant reductions in postmenopausal serum estrone, estradiol, free estradiol, and free testosterone and increases in SHBG. The weight loss interventions also significantly reduced insulin, C-reactive protein, and leptin and increased adiponectin. Exercise had little effect on sex hormones or the other potential breast cancer biomarkers.
Elevated blood estrogen and testosterone concentrations have consistently been associated with increased breast cancer risk, with doubling or greater effect on risk in women in the highest versus lowest quartiles or quintiles in prospective cohort studies.5,7,52,53
In one of these, Woolcott et al7
measured sex hormones in the same laboratory as for the present study and found that a doubling of free estradiol raised breast cancer risk by a factor of 2.26. Therefore, the 30% drop in free estradiol we observed with ≥ 5% of weight loss (achieved by 78% and 65% of the diet + exercise and diet groups, respectively) could be associated with a 22% decrease in breast cancer risk. Our participants' mean baseline estradiol concentration is in the top estradiol quartile range for the Woolcott study, and the diet and diet + exercise groups' mean 12-month values fall into the third highest quartile range. Because the odds ratio for breast cancer decreased from 6.4 to 2 in the fourth and third quartiles in that study, respectively, our weight loss intervention's decrease in mean estradiol could represent a ≥ 50% reduction in breast cancer risk. However, the results of these prospective cohort studies are based on a one-time sample, rather than serial samples. Therefore, our study suggests that a modest degree of weight loss could have a powerful effect on breast cancer risk; however, the impact of a reduction in sex hormones on breast cancer risk reduction is still unknown.
Low-fat dietary interventions without weight loss have reported either no or small change in estrogens.22–24,26,27,29,54
Two previous randomized controlled trials in postmenopausal women found modest reductions of 2% to 14% in estrogens after 1-year aerobic exercise interventions.19,20
In one of these, those exercisers who reduced percent body fat by more than 2% (mean absolute value) experienced a 15% decline in estradiol.19
A third 1-year randomized controlled trial found a significant lowering of testosterone in postmenopausal women randomly assigned to exercise who lost more than 2% body fat.21
In the present study, weight loss ≥ 5% was associated with significantly greater reductions in estradiol, free estradiol, and free testosterone and significantly increased SHBG. Taken together, these findings suggest that weight loss is the key factor linking alterations in diet or exercise to sex hormone changes. The effect of weight loss on estrogens may occur through a reduction in adipose tissue aromatase levels.10,55
In addition to being the first study to examine the effect of weight loss on sex hormones in postmenopausal women, the Nutrition and Exercise for Women Trial achieved greater adherence to a higher exercise goal and greater weight loss than the original Diabetes Prevention Program lifestyle intervention.36
The lack of effect of exercise alone does not agree with epidemiologic studies in which physical activity is associated with decreased risk of breast cancer.3,56
Therefore, exercise could play a role in reducing risk of postmenopausal breast cancer though different biologic mechanisms than were examined in this study. Exercise may also play a role in reducing breast cancer risk by augmenting dietary weight loss57
which will be critical for long-term risk reduction.1
Strengths of our study include a large sample size and long duration with excellent adherence and low attrition. The weight loss intervention was a group-based modification of the Diabetes Prevention Program intervention,36
which has publically available materials that have been tested in a variety of populations.59–63
This suggests that successful replication without the high costs of individually delivered weight loss programs is feasible. The exercise intervention, which consisted primarily of brisk walking, should be easily adoptable by most women in a clinical or community setting. However, the effects of these dietary weight loss and exercise interventions on breast cancer incidence are unknown.
Our study had some limitations. We tested only one dietary weight loss and one exercise intervention and cannot speculate on effects of other weight loss or exercise modalities. The study population was primarily non-Hispanic whites, and intervention effects in women from other race or ethnic groups cannot be inferred. Furthermore, the trial did not test whether weight loss or exercise reduced incidence of breast cancer, which would require a trial with a much larger scope.64
Total bone mineral density declined in all intervention groups, although the clinical significance of the change in total bone density is not defined.65
Future weight loss studies should consider the inclusion of resistance exercise to avoid loss of bone mass.65–68
The exercise group reported more musculoskeletal injuries than the diet and diet + exercise groups, which suggests that weight loss protects women from exercise-induced injury.69,70
The results of this study could be relevant even to women who choose to use breast cancer chemoprevention. Tamoxifen may have a lower breast cancer risk reduction effect in obese than normal weight women.71
Aromatase inhibitors, which have been found to reduce risk of new72
or recurrent breast cancer, had lower effectiveness in obese versus normal-weight patients in some,73
but not other,72,74
trials. Conditions that are increased with some of these agents, such as deep vein thrombosis and endometrial cancer, may be increased to a greater extent in obese than normal-weight women.71,75
Therefore, even for women who chose treatment with these agents, weight reduction if overweight or obese may be beneficial. Furthermore, although recent reports indicate that tamoxifen and raloxifene treatment confers long-term (10+ years) protection against breast cancer risk,76–80
the long-term efficacy of aromatase inhibitors on breast cancer risk reduction has not yet been established.72
Weight loss in overweight or obese women therefore represents an additional option for long-term breast cancer risk reduction.
In summary, a moderate degree of weight loss achieved through a reduced-calorie weight loss diet intervention reduced serum concentrations of estrogens, free testosterone, and other potential breast cancer biomarkers in overweight or obese postmenopausal women. These results have implications for the significant majority of postmenopausal women who are overweight or obese81,82
and therefore at elevated risk for breast cancer incidence2