The role of hormones in the etiology of human breast cancer

It has long been suspected that endocrine factors play a promoting or contributory role in the genesis of human breast cancer. Attempts to define and quantify such factors, however, have proven elusive. 1) Estrogens: Women at increased risk for breast cancer were shown to excrete less estriol (E3) vs estrone and estradiol. Conversely, women at low risk for breast cancer had higher urinary “estriol ratios.” These data led to the hypothesis that E3 is a “protective” estrogen. Recent studies of estriol production rates, its origin and circulating levels, however, have shown no differences in these crucial parameters in women with high E3 ratios vs low E3 ratios or in women with previous breast cancer. These data imply that high vs low urinary E3 ratios simply reflect different pathways of estrogen metabolism, and not differences in estrogen production. In women with established breast cancer, earlier studies of urinary estrogens as well as recent measurements of estrogen blood production rates have shown no significant abnormalities. Further, the contribution of androstenedione, estrone's principle prehormone, is normal in women with breast cancer. 2) Androgens: Earlier studies by Bulbrook in women with breast cancer correlated decreased urinary 17-KS with poor responses to endocrine ablative procedures. These workers also found low urinary etiocholanolane in women destined to develop breast cancer. Thus, decreased androgen excretion seems to be associated with poor response to endocrine therapy and increased risk for breast cancer. Similarly, dehydroepiandrosterone and its metabolites were found to be decreased in women with breast cancer. Androstenedione production, however, was found to be normal in women with post-menopausal breast cancer. The significance of androgen alterations in women with breast cancer (or at high risk) is still unclear. 3) Progesterone: No abnormalities in progesterone production have been reported in women with breast cancer. The Sherman-Korenman hypothesis that women with inadequate corpus luteum formation are at increased risk for breast cancer still requires confirmation. 4) Prolactin: Most reports to date indicate no abnormalities of prolactin in women with breast cancer. Henderson's data showing high plasma prolactin and estradiol in daughters of women with breast cancer (high risk) need confirmation. 5) Thyroid: In spite of several intriguing associations of thyroid function with steroid and peptide hormone metabolism, no consistent evidence has emerged implicating abnormal thyroid function in women with breast cancer. From the above, it is apparent that in spite of tantalizing bits of data linking breast cancer development with possible alteration of endocrine function, no clear-cut or comprehensible patterns are yet evident.