Blood concentrations of estrogen (estradiol) prior to the study or after hormone treatment did not predict therapeutic response. This suggests that the beneficial effects of estrogen aren't mediated by correcting abnormally low levels of the hormone. Rather, Schmidt and Rubinow suggest that some women may be especially sensitive to changing hormone levels. As with disorders like PMS and post-partum depression, such hormonal changes appear to be necessary, but not sufficient, to trigger perimenopausal depression, say the researchers, who are attempting to identify the still-unknown underlying predisposing factors. Doctors often prescribe estrogen to protect perimenopausal women from osteoporosis and heart disease, but long-term use of estrogen replacement may increase a woman's risk of breast and uterine cancer. In the future, more specific-acting medications that work through estrogen receptors may be engineered to selectively enhance bone, blood lipids and brain tissue without adversely affecting breast and uterine tissue, the researchers suggest.