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Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal

Comment by Professor Martha Hickey for the Australasian Menopause Society


Previous reports from the Women’s Health Initiative study, a large prospective randomized controlled trial of oral combined equine estrogen (premarin) and medroxyprogesterone acetate (provera), CEE alone or placebo in postmenopausal women have shown an increased risk of invasive breast cancer after long-term us of combined HRT. These findings have changed practice.

This new follow-up report from the WHI estrogen alone arm describes the longer term outcomes of 10,739 women with prior hysterectomy who had previously taken CEE or placebo for a median of 5.9 years and were then were followed up for a median of 10.7 years in total. The median duration of adherence (taking >80% of study pills) to CEE was 3.5 years. The main outcomes were CHD and invasive breast cancer. In addition, a global index of risks and benefits included CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, hip fracture, and death were reported.

 There are two principal messages from this study. The first is that the trend toward reduced incidence of invasive breast previously reported in CEE users continued after cessation, and reached statistical significance in this follow up study. The second key message is that risks associated with CEE use at follow up were essentially the same as those seen with placebo. Use of CEE for 6 years in postmenopausal women does not appear to be associated with any significant risks around 5 years after discontinuation, and is associated with a decreased risk of invasive breast cancer.

 In the overall study population, there was no significant effect of CEE on CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality Outcomes for the subgroup of women recruited at aged 50-59 were considered separately from older women who made up the great majority of those recruited to WHI (68% were over 60 years at recruitment). In these younger women, rates of cardiovascular disease were significantly reduced at follow up after CEE use. The authors comment that these findings are consistent with the ‘timing hypothesis” which suggests that initiation of estrogen during the early postmenopausal period may confer cardiovascular advantage. The findings of studies designed to address this hypothesis (such as KEEPS, the Kronos Early Prevention Study www.keepstudy.org) are awaited.

The clinical implications of these new data from WHI are that women considering HRT and their health care providers should consider age at initiation and hysterectomy status in addition to established risks and benefits during decision making. For women at all ages in WHI the risks associated with CEE use for 4-6 years appear to be very small. For younger women initiating CEE there may be cardiovascular benefits. For postmenopausal women of all ages there may be a reduction in breast cancer risk with CEE. However, this risk reduction in breast cancer risk is inconsistent with many other studies and the mechanisms of risk reduction are not known


LaCroix AZ, Chlebowski RT, Manson JE et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305:1305-1314. 

 Jungheim ES, Colditz GA. Short-term use of un JAMA, April 6, 2011—Vol 305, No. 13opposed estrogen. JAMA 2011;305:13 54-1355.

Content updated 18 April 2011

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