Low-dose estrogen therapy for menopausal women: a review of efficacy and safety.

BACKGROUND: Recent adverse events involving research of traditional estrogen therapy have led to interest in lower-than-standard doses of menopausal estrogen therapy.
METHOD: The Medline (1966-present) database was searched for randomized controlled trials (keywords: low-dose estrogen, minimum dose AND estrogen, menopause, and osteoporosis) regarding hot flashes, endometrial hyperplasia, vaginal bleeding, breast tenderness, and bone density. Studies are only a few years in duration.
RESULTS: The decrease in hot flashes with half-strength estrogens, range 60%-70%, is less than the 80%-90% reduction with standard dosing. Some low-dose preparations preserve lumbar and femoral bone density (although the degree of effect and quality of evidence vary among preparations). Bone density effects are dose dependent for conjugated equine estrogen (CEE), transdermal estradiol ethinyl (E(2)), norethindrone acetate (E(2)/NETA), oral E(2), and esterified estrogens. Bone preservation is likely to be less efficacious with low-dose estrogens than with traditional doses. Low-dose estrogen alone may not protect bone unless adequate calcium is given. Breast tenderness and skeletal effects are likely dose dependent. The longest endometrial safety data are 2-year data, reported for 5 microg/1 mg EE(2)/NETA and for 0.3 mg/day esterified estrogens. Some low-dose preparations have better vaginal bleeding profiles than do higher dose preparations. Breast tenderness is not totally averted with new lower-dose preparations. There are no fracture, breast cancer, or cardiovascular outcome data and a general lack of direct head-to-head comparisons involving low-dose preparations.
CONCLUSIONS: Serious adverse effects linked with traditional doses of estrogens may not be averted with lower-dose preparations, and low-dose preparations should not yet be emphasized as being safer than traditional (e.g., 0.625 mg/day CEE doses).