Menopause Live from IMS

LaCroix and colleagues [1] recently reported health outcomes after stopping therapy among postmenopausal women randomized to conjugated equine estrogens (CEE) in the estrogen-only arm of the Women’s Health Initiative. A total of 7645 women (78% of the original cohort) gave consent to be included in this follow-up over a mean duration of 10.7 years. Post-intervention use of estrogen replacement therapy (ERT) in the two groups was 3% and 2.7%, respectively. Post-intervention annualized rates comparing women originally randomized to CEE with those randomized to placebo were reported for the following conditions: coronary heart disease: hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.75–1.25; breast cancer: HR 0.75, 95% CI 0.51–1.09; stroke: HR 0.89, 95% CI 0.64–1.24; venous thrombosis: HR 0.63, 95% CI 0.41–0.98; hip fracture: HR 1.27, 95% CI 0.88–1.82. Over the entire follow-up period (i.e. the active treatment intervention phase and the post-intervention follow-up), the incidence of breast cancer was lower in the CEE group (HR 0.77, 95% CI 0.62–0.95).

Comment
The headline news from this paper reporting follow-up of the WHI estrogen-only trial [1] is the good news that there continued to be no increase in breast cancer risk. Just as the intervention arm of this study [2] showed no increased risk of breast cancer for users of ERT, the follow-up phase [1] confirmed this finding (HR 0.75, 95% CI 0.51–1.09) and, over both phases of this study, the incidence of breast cancer was significantly lower (HR 0.77, 95% CI 0.62–0.95).

However, the most important data to arise from this study was the unequivocal finding that, amongst women aged 50–59 years, there was no index event for which risk was increased and that there was a significant reduction in cardiovascular disease risk. 

In this age group, coronary heart disease risk was reduced (HR 0.59, 95% CI 0.38–0.90), myocardial infarction risk was reduced (HR 0.54, 95% CI 0.34–0.86), stroke risk was not increased (HR 1.09, 95% CI 0.65–1.83), and deep vein thrombosis was not increased (HR 0.71, 95% CI 0.40–1.26). Nor was there any increased risk of pulmonary embolus, breast cancer, colorectal cancer, or hip fracture. Risk of death from all causes was reduced, but not significantly (HR 0.73, 95% CI 0.53–1.00) as was the Global Index (HR 0.85, 95% CI 0.70–1.03).

In absolute terms, this translates into 12 fewer heart attacks, 13 fewer deaths and 18 fewer adverse events per 10,000 women per year for women who took CEE during the intervention phase of the trial.

This paper thus confirms the findings of earlier preclinical studies, observational studies, other reviews of WHI data and meta-analyses [3–8] that there is a ‘window of opportunity’ for the safe administration of estrogen replacement therapy around the time of the last menstrual period. Taken in its entirety, the WHI estrogen-only and follow-up studies [1,2] found no increase in any cancer, a decreased risk of coronary heart disease, a small increase in venous thromboembolism risk for current users of oral ERT and an overall improvement in the risk of death. They also confirm that there is a greater risk if treatment is initiated well after the last menstrual period, the Global Index being 0.85 (0.70–1.03) for 50–59-year-olds and 1.15 (1.01–1.32) for 70–79-year-olds.

The editorial [9] accompanying the initial WHI estrogen-only randomized trial bemoaned the fact that ‘previous available evidence had been misleading’. The editorial [10] accompanying the current paper suggests that the randomized, controlled trial is at fault and that observational studies are more likely to be correct. Both cannot be right and it is most likely that a properly designed, randomized, controlled trial and a properly designed observational study examining the same target populations will discover identical truths.

Rodney J. Baber
Associate Professor of Obstetrics and Gynaecology at The University of Sydney, Head, Menopause Unit, The Royal North Shore Hospital of Sydney, New South Wales, Australia

References
1. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy. JAMA 2011;305:1305-14.
http://www.ncbi.nlm.nih.gov/pubmed/21467283
2. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative randomized control trial. JAMA 2004;291:1701-12.
http://www.ncbi.nlm.nih.gov/pubmed/15082697
3. Clarkson TB. Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression. Menopause 2007;14:373-84.
http://www.ncbi.nlm.nih.gov/pubmed/17438515
4. Rossouw J, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since the menopause. JAMA 2007;297:1465-77.
http://www.ncbi.nlm.nih.gov/pubmed/17405972
5. Sturdee DW, Pines A; International Menopause Society Writing Group. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011;14: in press
6. Salpeter SR, Cheng J, Thabane L, et al. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women. Am J Med 2009; 122:1016-22.
http://www.ncbi.nlm.nih.gov/pubmed/19854329
7. Hodis HN, Mack WJ. Coronary heart disease and hormone replacement therapy after the menopause. Climacteric 2009;12(Suppl 1):71-5.
http://www.ncbi.nlm.nih.gov/pubmed/19811246
8. Postmenopausal hormone therapy: An Endocrine Society Scientific Statement. J Clin Endocrinol Metab 2010;95(Suppl 1):No 07.
http://www.endo-society.org/journals/scientificstatements/
9. Hulley SB, Grady D. The WHI estrogen-alone trial – do things look any better? JAMA 2004;291:1769-71.
http://www.ncbi.nlm.nih.gov/pubmed/15082705
10. Jungheim ES, Colditz GA. Short term use of unopposed estrogens: a balance of inferred risks and benefits. JAMA 2011;305:1354-5.
http://www.ncbi.nlm.nih.gov/pubmed/21467291