Estrogen Alone Poses No Increased Breast Cancer Risk

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SAN ANTONIO—A re-analysis of the Women’s Health Initiative (WHI)—which found an increased risk of breast cancer and heart disease in women taking hormone replacement therapy (HRT)—suggests that estrogen alone, without progesterone, may actually be protective against breast cancer. 

“This information was downplayed by the WHI at the time. We analyzed the two trials and did tests for interactions, comparing estrogen alone with estrogen plus progestin. We found a significant reduction in risk of breast cancer with estrogen alone, compared with a significant increase with the hormonal combination,” said Joseph Ragaz, MD, of the University of British Columbia’s School of Population and Public Health, Vancouver, Canada, who reported findings at the 33rd annual San Antonio Breast Cancer Symposium.                     

The combined studies involved more than 25,000 healthy women. The first WHI trial (WHI1) evaluated estrogen (Premarin 0.625 mg/day) plus progestin (Provera 2.5 mg/day) versus placebo, and the second (WH2), which was limited to women without a uterus, evaluated estrogen alone (Premarin 0.625 mg/day) versus placebo. A comparative analysis assessed breast cancer rates between the two studies and according to the women’s risk for breast cancer (Gail score), hormone use before the study, and other factors.


”The study found that HRT based on estrogen alone was significantly protective against the development of breast cancer, reducing the incidence by 20%; combined HRT, on the other hand, actually increased the risk by 25%,” he said. 

By Gail score, women at low-to-medium risk (<1.75 score) had a relative risk reduction of 29% with estrogen alone, while on estrogen plus progestin their risk increased by 25%, Ragaz reported.

In women without any previous hormone use, estrogen alone was significantly more protective, with a 34% reduction in events. Estrogen plus progestin was associated with a 16% increased risk, he added. 

A subset of patients had a low risk for developing breast cancer, based on Gail score <1.75, no previous HRT before the study, no positive family history of breast cancer, and no personal history of benign breast disease. In these women, the risk of developing breast cancer was reduced by 20% altogether, and by as much as 43% if they had no history of benign breast disease. 

In addition, estrogen alone, at least in some age groups, was significantly protective against coronary heart disease, colorectal cancer, and hip fracture, Ragaz added. 

“A prospective evaluation of HRT is now required to establish the best regimens and formulation of HRT based on estrogen alone, and with or without a safer new progestin combination,” Ragaz said. “It is very important to look into new generation progestins that are more natural.” New compounds—one is called prometrium—are in development, he said.

Based on these findings, he believes that for a subset of women aged 60 and younger estrogen alone might be safely used. In particular, these would be younger women who had undergone hysterectomy and did not need the protective effect of progestin against endometrial cancer

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Last modified: July 22, 2021