Conjugated estrogens and breast cancer risk

Available epidemiologic data suggest the possibility that the use of oral c onjugated equine estrogens (CEE) 0.625 mg/day as a first-choice dose could be associated with a very limited (if any) breast cancer risk increase. Som e biological peculiarities of oral CEE back the possibility of a limited de trimental effect on breast tissue, due to either direct or indirect actions . Direct actions. Some experimental findings suggest that the 17 alpha-dihydr oderivatives of equilenin and equilin (15% of the CEE components) have a no n-estrogenic or even an anti-estrogenic effect on breast tissue. This could partially counterbalance the stimulatory action of the other CEE component s. Indirect actions. Oral estrogens, through their metabolic and hepatocellula r effects (emphasized by the first liver passage) cause a sharp increase in sex hormone binding globulin (SHBG) level which is followed by a lower qua ntity of both estrogen and androgen in the free, bioavailable, form. More i mportantly, they cause a decrease in circulating insulin-like growth factor I (IGF-I) activity, due to both a reduction in IGF-I synthesis by the live r and an increase in IGF-binding protein-1 level. A strong relationship bet ween breast cancer risk and the concentration of circulating IGF-I in preme nopausal women has been recently found. Actually, estrogens and IGF-I have a synergistic effect on cell proliferation, and IGF-I is necessary for maxi mum estrogen-receptor activation in breast cancer cell lines. The possibili ty does exist that the SHBG level increase and the IGF-I bioavailability de crease, caused by oral CEE, balance the increased estrogen stimulation on b reast tissue.