Selective estrogen receptor modulators (SERMs) are structurally diverse com
pounds that bind to estrogen receptors (ER) and elicit agonist or antagonis
t responses depending on the target tissue and hormonal milieu. They are be
ing evaluated primarily for conditions associated with aging, including hor
mone-responsive cancer, osteoporosis and cardiovascular disease. Several SE
RMs are marketed or are in clinical development, including triphenylethylen
es (tamoxifen and its derivatives: toremifene, droloxifene and idoxifene),
chromans (levormeloxifene), benzothiophenes (raloxifene, LY353381) and naph
thalenes (CP336,156). Tamoxifen and toremifene, both used to treat advanced
breast cancer, also have beneficial effects on bone mineral density and se
rum lipids in postmenopausal women. Tamoxifen was recently shown to decreas
e the risk of invasive breast cancer in women at high risk. Unfortunately,
both drugs also have stimulatory effects on the endometrium. Raloxifene, us
ed for prevention of postmenopausal osteoporosis and fragility fractures, a
lso has favourable effects on bone mineral density, serum lipids and the in
cidence of invasive breast cancer in postmenopausal women but does not stim
ulate the endometrium. Like replacement estrogens, SERMs increase the risk
of venous thromboembolism. SERMs offer postmenopausal women many of the adv
antages of estrogen replacement while mitigating some of the disadvantages,
particularly the concern over breast cancer. Newer SERMs, exemplified by r
aloxifene, also eliminate the concerns over endometrial stimulation that we
re not addressed by first generation SERMs. The clinical success of SERMs h
as set the stage for a variety of drug therapies based on selective modulat
ion of nuclear receptor activity.