As more and more information comes in from large-scale trials, it is clear that estrogen replacement therapy in the usual form of an estrogen plus a progesterone drug (E+P), commonly called hormone replacement therapy or HRT, increases the risk of breast cancer.When the results from the "definitive" randomized trial, the Women's Health Initiative (WHI) study, were announced in 2002 and showed about 25 percent more breast cancers with E+P compared with placebo, the use of HRT plummeted. A few years later, this became evident with fewer breast cancers diagnosed, reversing a longstanding trend of rising rates.However, the estrogen receptor is expressed in many other tissues besides the breast, so further analyses of this trial looking at other cancers showed interesting effects--such as a higher death rate from lung cancer with E+P, but interestingly, a lower risk of colorectal cancer.Just this month, a group at the University of North Carolina, using a less reliable case-control design, found the lower end of colon and rectal cancer risk has halved with any HRT use. However, on further follow-up of the WHI study, it turns out that the colorectal cancer cases on E+P were of higher stage, so that there were actually more deaths from colorectal cancer on replacement therapy. Finally, E+P also increased the risk of stroke and blood clots in the lung and appeared to raise the chance of heart attacks, especially in the first year of therapy. It did lower hip fracture rates, in keeping with its bone density-enhancing properties.So clearly, E+P causes more cancers and does not, as initially thought, protect the heart. Even though there are still detractors who criticize the trial design--the age at which patients were started on therapy and the exact form of therapy--one wonders if there is at all a silver lining in this story.Well, there might be--and that is therapy with estrogen alone. This therapy can only be given to women who have had their uterus removed. In women who do have a uterus, estrogen-only therapy can cause a build-up of the uterine lining and raises the uterine cancer risk. (Women with a uterus receive E+P because adding progesterone reduces that risk of uterine cancer).The WHI study also randomized more than 10,000 women who had prior hysterectomy and gave them either estrogen alone or placebo. In this trial there were actually fewer cases of breast cancer, not quite statistically significant, though. There was no effect on colorectal or lung cancers. There were also slightly fewer stokes and heart attacks, but more clots to the lung; however none of these were statistically different.So, it is possible that estrogen might be a useful drug in women without a uterus, but clotting problems are still a concern. We have seen the emergence of designer anti-estrogen drugs like raloxifene (approved for breast cancer reduction and osteoporosis), and more recently lasofoxifene, an investigational drug found to lower fracture, breast cancer, stroke, heart attacks, but increased clots.Manipulating the hormonal milieu is a tricky proposition, but future generations of "estrogen modulators" might just strike the right balance for multiple health effects.For more on HRT and the risk of breast cancer, read "The HRT Connection" from Fall 2007.