Plasma estrogen suppression with aromatase inhibitors evaluated by a novel, sensitive assay for estrone sulphate

Aromatase inhibition is a well-defined treatment option for postmenopausal breast cancer. Although several aromatase inhibitors such as aminoglutethimide, formestane and fadrozole have been found to inhibit in vivo aromatization by >85%, previous studies reported plasma estrogen levels to be sustained at approximately 20-50% of their control level during treatment with these drugs. The discrepancy could be due to lack of sensitivity or non-specific crossreactions in the radioimmunoassay (RIA) methods. Mean plasma levels of estrone (E1) and estradiol (E2) in postmenopausal women are approximately 80 and 20 pmol/l, respectively; on the contrary, mean plasma levels of the estrogen conjugate estrone sulphate (E1S) are approximately 4-500 pmol/l. Most RIA methods for plasma E2 and E1 measurements have sensitivity limits in the range of 2-3 and 7-10 pmol/l, respectively; accordingly, the suppression of plasma estrogens by more than 80-90% will produce hormone values below the sensitivity limit of the method in many patients. Recently, we developed a new method to determine plasma E1S. This assay has a sensitivity limit of 2.7 pmol/l. In theory, this method may allow the determination of plasma E1S levels suppressed to less than 2% of control values in the majority of patients. Using this method, we found different aromatase inhibitors such as formestane, aminoglutethimide, formestane and aminoglutethimide administered in concert or anastrozole to suppress plasma E1S levels down to 24, 13, 7 and 4%, respectively. The suppression of plasma E1S evaluated with this method thus approaches the percentage aromatase inhibition measured with tracer studies.