Study reaffirms tamoxifen's dark side.

Tamoxifen, a synthetic hormone often prescribed to treat breast cancer, can cause potentially malignant changes in the endometrium, or uterine membrane, of healthy postmenopausal women, researchers confirm in a new study.

Other studies have linked tamoxifen to increased risk of endometrial cancer (SN: 4/16/94, p.247). However, this is the first randomized, placebo-controlled trial of tamoxifen's effects on the uterus and ovaries of this group of women, Rajendra P. Kedar of King's College School of Medicine and Dentistry in London and his colleagues assert.

"They are the first," agrees Urania Magriples of Yale University School of Medicine. "It's amazing someone hasn't done something like this before." Sohaib Khan of the University of Cincinnati College of Medicine says the study is more carefully done than others, but "I don't think they really reached anything new."

Several ongoing studies are examining whether tamoxifen might help prevent breast cancer in healthy women with a family history of the illness. To see if the drug causes endometrial changes, Kedar and his colleagues studied 111 women age 45 to 71 who took either tamoxifen or a placebo as part of one of these trials, they report in the May 28 LANCET.

Using a vaginal ultrasound probe, they measured the size of each woman's uterus and the thickness of her endometrium. The scientists also biopsied the endometrium and measured blood flow to the tissue, which if elevated may indicate an increased risk of cancer.

"Our study detected endometrial abnormalities at various times from the first tablet of tamoxifen," Kedar and his colleagues state. Kahn, however, questions whether the drug can cause such rapid changes.

The endometrium appeared abnormally thick in 24 of 61 women taking tamoxifen; in 10 of these 24 women, endometrial cells underwent potentially precancerous changes. Only 5 of the 50 women given a placebo had an abnormal endometrium and none showed the cell changes. Five women taking the drug and one volunteer on placebo developed a polyp; the significance of this is not clear. Overall, women taking tamoxifen had a larger uterus and higher blood flow to that organ than those not taking the drug.

Researchers now understand better how tamoxifen helps prevent breast cancer. Investigators have known that the drug binds to estrogen receptors. Normally, estrogen turns on these receptors, which activate the genes important in events that can lead to cancer.

Tamoxifen, however, fails to turn on the receptors, and the new study, in the June 3 SCIENCE, suggests why. The drug keeps the receptors from hooking up with a protein, ERAP 160, that they need to function, report Myles Brown of the Dana-Farber Cancer Institute in Boston and his colleagues.