n the vexed question of the safety of hormone (estrogen) replacement therapy or HRT, a gathering of experts in Milan, Italy earlier this year concluded that there was a small increase in absolute risk of breast cancer arising in women on HRT which faded once they stopped hormone treatment. This has to be added to the known risk of endometrial cancer. The benefits–apart from effects on menopausal symptoms such as hot flashes–include prevention of cardiovascular risk factors and bone strengthening. Judging the balance of risk and benefit, in the form of advice to patients, is greatly exercising physicians at present. Enter the so-called "designer estrogens" or selective estrogen-receptor modulators (SERMs).

   Among the SERMs, raloxifene (Evista) is the one on which most clinical research has been done, but there are others in the pipeline, and one can already read of "third-generation SERMs" and of the search for the perfect agent beyond raloxifene. Prof. Pierre D. Delmas from the Universite Claude Bernard, Lyons, France, a participant in the Milan expert meeting and lead author on paper #6, tells Science Watch that this 1997 article was "...the first one showing the effect of a SERM in postmenopausal women." This, he added, was "a new concept (estrogen analogs with either estrogen agonist or antagonist effect according to the target tissue)" and one that "led to the clinical use of raloxifene, which is now on the market throughout the world."

   What physicians want to know is whether SERMs prevent osteoporosis and the fractures that accompany that condition and prevent cardiovascular disease, and whether they do so safely, in view of concerns expressed about conventional HRT. But one step at a time. Delmas and his colleagues randomized 601 postmenopausal women to one of three doses of raloxifene or to placebo for two years, and they then measured bone density and cholesterol concentrations and also looked at endometrial thickness with an ultrasound probe.

   Changes in bone mineral density of around 1% may seem rather subtle to the non-physician, but density declined in the control group by 0.6% while it rose, in dose-related fashion, in women on raloxifene by 1.2, 1.4, and 1.9%. Furthermore, all the women took calcium supplements, which could have affected bone mineral in all four groups, thus perhaps hiding part of the relative improvement achievable by the drug. Serum total cholesterol fell, again with a dose relationship, in patients on the active drug.

   Endometrial thickness data are not recorded in detail in the study by Delmas et al., but no change was noted in the six-monthly scans. Confirmation of that comes from a paper recently published in Menopause (6:188-95, 1999), where G.C. Davies and coworkers report that raloxifene given at doses of 60 mg daily for up to 30 months to postmenopausal women was "not associated with vaginal bleeding or increased endometrial thickness."