Estrogen alone not to blame in HRT

Hormone may work with progestin, genetics to raise disease risk

By | April 12, 2006

Exogenous estrogen by itself does not raise the risk of breast cancer among women who have had a hysterectomy, and appears to even reduce the risk of some types of the disease, according to findings from the Women's Health Initiative released in the Journal of the American Medical Association (JAMA) this week. The authors suggest that progestin -- a synthetic progesterone already blamed for a number of diseases -- may be the culprit in the increase in cancer rates following hormone replacement therapy (HRT) that combines estrogen and progestin. Wulf Utian, executive director of the North American Menopause Society, who did not participate in the research, suggested the increase in breast cancer following HRT may relate to timing of mitotic activity triggered by progestin, which normally takes place only in the latter half of the menstrual cycle. Alternatively, WHI project officer Jacques Rossouw, of the National Heart, Blood, and Lung Institute (NHBLI), not a co-author, told The Scientist the effect may not be due to progestin alone, but to its synergy with estrogen. According to the new report, exogenous estrogen appeared to reduce the risk of breast cancer in nearly 11,000 women who had undergone a hysterectomy, especially the risk of early-stage disease and ductal carcinoma, the most common type. This result appears to contradict a previous report from the WHI, a trial of conjugated equine estrogens combined with progestin. In menopausal women with a uterus, the combined therapy -- prescribed for women with uteruses because unopposed estrogen raises the risk of uterine cancer -- was associated with a significant increase in breast cancer. Another WHI study published this week showed that exogenous estrogen alone raised the risk of blood clots. But the blood clot risk was -- like the breast cancer risk -- higher in women taking combination hormones. The study also revealed potentially useful information about the genetics that drive cancer. Risk in the breast cancer study was lowest in women already at low risk and higher in women with affected first-degree relatives, suggesting that exogenous estrogen interacts with genetic variation to shape breast cancer risk. Marcia Stefanick of Stanford University, first author of today's paper, said that's a fair, but preliminary, interpretation. Researchers need to "reconsider what is going on with estrogen and breast cancer within the context of genetic factors and other factors," she said. Garnet Anderson, the paper's second author, of the Fred Hutchinson Cancer Research Center in Seattle, is participating in a whole genome scan study involving 1000 breast cancer patients and 1000 controls. A collaboration with Perlegen Sciences of Mountain View, Ca., it began with a Perlegen chip containing 350,000 single nucleotide polymorphisms (SNPs) from the women. Eventually the investigators expect to narrow their search to an estimated few hundred SNPs of potential interest. In the third stage, scheduled to happen next year, they will examine how those genes interact with hormones. During the study, WHI investigators collected blood from 160,000 study subjects along with extensive data about their health and other details. This year NHBLI opened up this trove -- and $17.5 million in funding -- to proposals from outside researchers. Deadline for first-round proposals has passed, but a second round of funding is planned for 2008. Details are to be available next year on the WHI Scientific Resources Web site. "These are amazing resources because we know so much about the women," Anderson told The Scientist. Tabitha M. Powledge Links within this article Marcia L. Stefanick, et al. "Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA, April 12, 2006 WHI Scientific Resources Web site Tabitha M. Powledge. "Hormone therapy in rehab," The Scientist, November 17, 2003. North American Menopause Society Writing Group for the Women's Health Initiative Investigators. "Risks and benefits of estrogen plus progestin in healthy women," JAMA, July 17, 2002. PM_ID: 12117397 J. David Curb, et al. "Venous thrombosis and conjugated equine estrogen in women without a uterus," Archives of Internal Medicine, April 10, 2006 Marcia Stefanick Garnet Anderson

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