Hormone replacement therapy in menopausal women: Past problems and future possibilities

Oral administration of conjugated equine estrogens (CEE) with and without the synthetic progestin medroxyprogesterone acetate (MPA) in postmenopausal women is associated with side-effects that include increased risk of stroke and breast cancer. The current evidence that transdermal administration of estradiol may provide a safer alternative to orally administered CEE is reviewed. Transdermally administered estradiol has been shown to be an efficacious treatment for hot flushes possibly without the increase in blood clotting that is associated with administration of oral CEE. Further, natural progesterone may have a more beneficial spectrum of physiological effects than synthetic progestins. The substantial differences between CEE compared with estradiol and estriol, as well as the differences between synthetic MPA and natural progesterone, are detailed. Estriol is an increasingly popular alternative hormone therapy used for menopausal symptoms. There is evidence that estriol, by binding preferentially to estrogen receptor-β, may inhibit some of the unwanted effects of estradiol. New clinical trials are needed to evaluate the safety and efficacy of topically or transdermally administered combinations of estradiol, estriol and progesterone. Future studies should focus on relatively young women who begin estrogen supplement use near the start of menopause.