Women's Health Initiative
The Women's Health Initiative (WHI) was initiated by the U.S. National Institutes of Health (NIH) in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women. In particular, randomized controlled trials were designed and funded that address cardiovascular disease, cancer, and osteoporosis.
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[edit] Study components
There are actually 4 different randomized interventions and a separate observational-only cohort in the WHI. All 4 of the randomized components overlap with each other to some extent (and a few even overlap with the observational study). The 4 interventions and their abbreviated terminology are:
[edit] Estrogen-progestin versus placebo
This phase studied estrogen, specifically conjugated equine estrogen, plus progestin (Prempro, Wyeth) compared to placebo (the "WHI-E+P" trial), among healthy postmenopausal women.
This trial found that, compared with placebo, women receiving estrogen plus progestin experienced:[1]
- increased risk of myocardial infarction ("heart attack")
- increased risk of stroke
- increased risk of blood clots, including deep venous thrombosis (DVT) and pulmonary embolism (PE)
- increased risk of breast cancer
- decreased risk of colorectal cancer
- fewer fractures
The trial was ended early in 2002 when the researchers found that the subjects with estrogen plus progestin had a greater incidence of coronary heart disease, breast cancer, stroke, and pulmonary embolism than the subjects receiving placebo.[2] Hormone replacement therapy use declined in the U.S. and around the world, followed by a decline in breast cancer.[3]
[edit] Conjugated estrogen versus placebo
This trial studied estrogen, specifically conjugated equine estrogen (Premarin, Wyeth), alone versus placebo (the "WHI-CEE" trial) in women with prior hysterectomy.
The trial was conducted among women with hysterectomy so that estrogen could be administered without a progestin. In women with a uterus, a progestin is needed to counteract the risk of endometrial cancer posed by unopposed estrogen.
Major results of this study were that, compared with placebo, women receiving estrogen alone experienced:[1]
- no difference in risk for myocardial infarction
- an increased risk of stroke
- an increased risk of blood clots
- an uncertain effect on breast cancer risk
- no difference in risk for colorectal cancer
- a reduced risk of fracture
[edit] Calcium and vitamin D versus placebo
This trial compared calcium plus vitamin D versus placebo ("WHI-CalcVitD"). It had two primary endpoints:
- Colorectal cancer endpoint: Long term daily supplementation of calcium with vitamin D had no effect on the incidence of colorectal cancer among postmenopausal women.[4]
- Fracture endpoint: Long term daily supplementation of calcium with vitamin D resulted in a small but significant improvement in hip bone density, but did not significantly reduce the number of hip fractures, and increased the risk of kidney stones.[5]
A secondary endpoint was postmenopausal weight gain. Long term daily supplementation of calcium with vitamin D resulted in a small prevention of weight gain.[6]
[edit] Non-intervention cohort
The non-interventional observational cohort study ("WHI-OS") observed 93,000 women drawn from the same national clinical coordinating centers (many epidemiology studies conducted within this observational component of the WHI).
The WHI Postmenopausal Hormone Therapy Trials were part of the effort to address the high risk of cardiovascular disease in older women. By the early 1990s, many physicians had come to interpret results from previous clinical trials and studies using experimental animals as indicating that administration of an estrogen supplement to postmenopausal women would lower the incidence of cardiovascular disease. Two hormone clinical trials were designed and conducted:
The estrogen that was administered in the WHI studies was conjugated equine estrogen (CEE). This consists of a mixture of estrogens isolated from horse urine (Premarin). The CEE was administered orally. Both studies were randomized, placebo-controlled studies. Half the women were given an inactive placebo rather than hormone(s). Both studies were terminated early because a reduction in cardiovascular disease was not observed for most women and some women had dangerous side-effects. In particular, an increased risk of dangerous blood clotting is associated with oral administration of CEE. A review of the observational and WHI estrogen trial results describes potential explanations for the conflicting results.
In addition, co-administration of MPA (medroxyprogesterone acetate, a type of progestin) with CEE was associated with a slightly increased risk of breast cancer. Some benefits of using an estrogen supplement such as reduced risk of bone fractures were confirmed by these studies. However, for the older postmenopausal women who were recruited for this study, the undesirable side-effects of treatment generally were greater than the health benefits. Based on the results of these studies, CEE and MPA are no longer given to women in order to try to prevent cardiovascular disease in older women. Younger postmenopausal women seeking relief from conditions such as hot flashes, sleep disturbance and urinary/vaginal atrophy are still candidates for hormone replacement therapy. Alternatives to orally administered CEE and MPA are being increasingly used by women since the termination of the WHI studies. For example, other forms of estrogen (such as esterified estrogens) or topical administration of estradiol may reduce the risk of blood clotting compared to that for oral CEE.[7]
Finally, the low fat dietary pattern trial of the WHI yielded conflicting and controversial results. However, the WHI trial has been argued as unnecessary by many scientists, who already knew a full decade ago that total fat intake is not related to cardiovascular risk nor postmenopausal breast cancer risk.
[edit] Criticisms
The dietary trial has been criticized by epidemiologists for its lack of validity, both internal (the desired endpoint for fat reduction in diet was not fully achieved)[8] as well as external (a group of post menopausal women is not generalizable to all women).[9] Finally, the mechanism of disease of developing breast cancer may have a significantly longer time course than the duration of the study,[10] and intervention may have been most effective prior to menopause.[11]
[edit] Footnotes
- ^ a b "Questions and Answers About WHI Postmenopausal Hormone Therapy Trials, NHLBI, WHI". http://www.nhlbi.nih.gov/whi/whi_faq.htm. Retrieved 2010-01-15.
- ^ Writing Group for the Women's Health Initiative Investigators (2002). "Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial". JAMA 288 (3): 321–333. doi:10.1001/jama.288.3.321. PMID 12117397. http://jama.ama-assn.org/cgi/content/abstract/288/3/321.
- ^ Chlebowski, RT; Kuller LH; Prentice RL; Stefanick ML; Manson JE; Gass M; et al. (2009). "Breast cancer after use of estrogen plus progestin in postmenopausal women". NEJM 360 (6): 573. doi:10.1056/NEJMoa0807684. PMID 19196674. http://content.nejm.org/cgi/content/full/360/6/573.
- ^ Calcium plus vitamin D supplementation and the risk of colorectal cancer. Wactawski-Wende J, et al; Women's Health Initiative Investigators. N Engl J Med. 2006 Feb 16;354(7):684-96.
- ^ Calcium plus vitamin D supplementation and the risk of fractures. Jackson RD, et al; Women's Health Initiative Investigators. N Engl J Med. 2006 Feb 16;354(7):669-83.
- ^ Calcium plus vitamin D supplementation and the risk of postmenopausal weight gain. Caan B, et al. Arch Intern Med. 2007 May 14;167(9):893-902.
- ^ Straczek C, Oger E, Yon de Jonage-Canonico MB, et al. (2005). "Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration". Circulation 112 (22): 3495–500. doi:10.1161/CIRCULATIONAHA.105.565556. PMID 16301339.
- ^ "Low-Fat Diet Not a Cure-All: Nutrition Source, Harvard School of Public Health". http://www.hsph.harvard.edu/nutritionsource/low_fat.html. Retrieved 2008-03-28.
- ^ Aberegg SK, Majure DT (2006). "Low-fat diet and cardiovascular disease". JAMA 296 (3): 280; author reply 280–1. doi:10.1001/jama.296.3.280-a. PMID 16849659.
- ^ Ravdin PM, Cronin KA, Howlader N, et al. (2007). "The decrease in breast-cancer incidence in 2003 in the United States". N. Engl. J. Med. 356 (16): 1670–4. doi:10.1056/NEJMsr070105. PMID 17442911.
- ^ Michels KB (2006). "The women's health initiative--curse or blessing?". Int J Epidemiol 35 (4): 814–6. doi:10.1093/ije/dyl133. PMID 16847020.
[edit] References
- Rossouw JE, Anderson GL, Prentice RL, et al. (2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial". JAMA 288 (3): 321–33. doi:10.1001/jama.288.3.321. PMID 12117397.
- Anderson GL, Limacher M, Assaf AR, et al. (2004). "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial". JAMA 291 (14): 1701–12. doi:10.1001/jama.291.14.1701. PMID 15082697.
