New research is shedding light on why estrogenic hormones produce unintended results in women, giving hope to the idea that new drugs might reach their targets and work more effectively. Ultimately it could mean that postmenopausal women would know that hormone-replacement therapy would have only its intended result.
"It's very difficult right now for women to make a choice about taking estrogen or other estrogen-like compounds, and, I think, it's equally difficult for physicians to try to tell women what they should do," said Ann M. Nardulli, a professor in the department of molecular and integrative physiology at the University of Illinois at Urbana-Champaign.
Nardulli was the principal investigator of a study published in the Jan. 7 issue of the Journal of Biological Chemistry. In the study, Nardulli, doctoral student Jennifer R. Schultz and postgraduate researcher Larry N. Petz added fuel to the argument that the long-held model for how an estrogen receptor binds to DNA and, in turn, regulates gene transcription is need of retooling.
Nardulli's team has found four discrete regions of the human progesterone receptor gene that confer hormone responsiveness. In the study, the activities of estradiol, tamoxifen, raloxifene and the soy phytoestrogens genestein and daidzein were examined and compared in uterine, mammary and bone cell lines. The researchers found vast differences based on the four regions.
"The model has always been that the estrogen receptor binds to DNA to activate transcription, but now we show that that's not always the case," Nardulli said. "Binding doesn't occur equally well in different kinds of tissue, and it requires a broader vision on how transcription changes the functions in cells."
The value of hormone-replacement therapy has come under scrutiny because of links to various cancers. It's also been discovered that women taking tamoxifen to protect against a relapse of breast cancer were more susceptible to getting uterine cancer. Other research, conducted at Illinois by food scientist William Helferich, has shown that the soy phytoestrogen genestein in doses similar to that found in supplements may negate the ability of tamoxifen to stop cancer redevelopment. Many women take soy supplements to control hot flashes.
The discovery in 1996 of a second estrogen receptor, or binding protein, began to rewrite conventional wisdom. Instead of just one receptor, now known as ER-alpha, researchers began studying the second one, ER-beta. ER-alpha is predominant in the uterus, liver, mammary gland, bone and cardiovascular systems; ER-beta is most expressed in the prostate, ovary and urinary tract.
Researchers also have found that many estrogen-responsive genes don't have estrogen response elements -- long considered the cornerstone of estrogen receptor binding and transcription. Instead, as in the human progesterone receptor gene, they have multiple binding sites for activator proteins such as the four regions identified in Nardulli's lab.