Estrogens, progestins, and risk of breast cancer

Obesity is associated with a decreased risk of breast cancer in premenopausal women but an increased risk in postmenopausal women, an effect that increases with time since menopause. Analysis of these effects of obesity shows that there is a ceiling to the carcinogenic effect of estrogen on the breast; increases in nonsex hormone-binding globulin-bound estradiol (non-SHBG bound E2) exceeding approximately 10.2 pg/ml have no further effect on breast cancer risk; this ceiling is lower than the lowest level seen during the menstrual cycle. This suggests that the effects of menopausal estrogen therapy (ET) and menopausal estrogen-progestin therapy (EPT) on a woman's breast cancer risk will greatly depend on her body mass index (BMI; weight in kilograms/height in meters squared, kg/m2) with the largest effects being in slender women. Epidemiological studies confirm this prediction. Our best estimates, per 5 years of use, of the effects of ET on breast cancer risk is a 30% increase in a woman with a BMI of 20 kg/m2 decreasing to an 8% increase in a woman with a BMI of 30 kg/m2; the equivalent figures for EPT are 50% and 26%. The analysis of the effects of estrogen also shows that even reducing the dose of estrogen in ET and EPT by as much as a half will have little or no effect on these risks. Reducing the progestin dose is likely to significantly reduce the risk of EPT: this is possible with an endometrial route of administration.