Women's Health Initiative
The Women's Health Initiative (WHI) was initiated by the 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, clinical trials were designed and funded that address cardiovascular disease, cancer, and osteoporosis.
Additional recommended knowledge
An outline of the WHI interventions and 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:
Estrogen plus progestin vs. placebo (the “WHI-E+P” trial), among healthy postmenopausal women.
Interesting notes about this trial:
- This trial component was abruptly stopped early in 2002 for exceeding global index of adverse events
- This was the trial that found the null results for estrogen and CHD, resulting in the worldwide decline in use of HRT.
- However, virtually every single endpoint was exactly predicted from observational cohort studies (including the major endpoints of breast cancer (BC), stroke, colorectal cancer (CRC), fracture, and more) —all except coronary heart disease (CHD).
Conjugated equine estrogen vs. placebo (“WHI-CEE” trial), among women with prior hysterectomy:
- The CEE trial was conducted among women with hysterectomy; thus, the women didn’t need progestin to counteract the uterine cancer risk of estrogen.
- CEE therapy interestingly was not associated with risk of breast cancer
- When one mentions the “estrogen” results in WHI, one must be very careful which estrogen trial is being referred.
Low fat dietary pattern (WHI-LowFat). This had 4 major papers that arose from it so far (all published in JAMA 2006):
- Weight loss endpoint
- Invasive BC endpoint
- Invasive CRC endpoint
- CVD endpoint(s)
Calcium + VitaminD combination vs. placebo (WHI-CalcVitD). This had 2 major papers arise from it in NEJM 2006, and one in May 2007 in the Archives of Internal Medicine :
- CRC endpoint
- Fracture endpoint
The non-interventional observational cohort study (WHI-OS) of 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.
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. A review of the WHI low fat trial describes methodologic issues in more detail.
- ^ J. E. Rossouw et al "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial" in Journal of the American Medical Association (2002) Volume 288, pages 321-333. Entrez PubMed 12117397
- ^ G. L. Anderson et al "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial" in Journal of the American Medical Association (2004) Volume 291, pages 1701-1712. Entrez PubMed 15082697
- ^ C. Straczec, et al "Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration" in Circulation (2005) Volume 112, pages 3495-500. Entrez PubMed 16301339
- hormone replacement therapy
- National Health Lung and Blood Institute's WHI website