Understanding the complex relationship between
obesity and
breast cancer is fundamental to our knowledge of the etiology of this
malignancy; changes in the composition of the hormonal milieu are implicit in this process.
Estrogens are synthesized from
androgens by
aromatase in the gonads and in peripheral tissues, principally, adipose tissue.
Obesity in women, regardless of their age, leads to more
aromatase and more extra-glandular
estrogen production. In postmenopausal women, in whom ovarian
estrogen production is absent, the increased incidence of
breast cancer in women with high body mass index has been attributed to the relatively high plasma levels of
estradiol from subcutaneous fat. In contrast,
obesity in premenopausal women is associated with a previously unexplained reduced incidence of
breast cancer. In obese premenopausal women, the cumulative effect of higher levels of
estrogens synthesized in the peripheral tissues, together with ovarian
estrogen production, results in a negative feedback on the hypothalamic pituitary controlled release of gonadotrophins and a resultant diminution in ovarian
steroid production. As a consequence, the normal balance of
estrogen and
progesterone levels is disrupted: while
estrogen levels are normalized,
progesterone production is markedly decreased.
Progesterone is a promoter of proliferation in the breast. The low levels of
progesterone in obese premenopausal women are consistent with, and we propose, are responsible for, the reduction in
breast cancer incidence in these women.