The
Women's Health Initiative (WHI) was initiated by the U.S.
National Institutes of Health (NIH) in 1991. The Women's Health Initiative consisted of clinical trials and observational research conducted to address major health issues causing morbidity and mortality in postmenopausal women. In particular,
randomized controlled trials were designed and funded that addressed
cardiovascular disease,
cancer, and
osteoporosis. In its entirety, the WHI studied more than 160,000 postmenopausal women aged 50-79 years over 15 years.
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-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]
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]
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
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]
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.
Criticisms
Upon halting the estrogen-progestin study in women with a uterus in 2002, many women feared using hormone replacement due to the risks of heart disease and breast cancer. Many postmenopausal women stopped their hormone replacement in the mid 2000's with the release of results from the WHI and subsequently the incidence of breast cancer was reduced by thousands of women each year. Despite the reduction in the incidence of breast cancer, experts questioned the applicability of the WHI to the general population.
Women enrolled in the WHI were 63 years old on average, asymptomatic, and on average a decade had passed since the onset of their menopause. Furthermore, the focus of the WHI study was disease prevention. Most women take hormone replacement therapy to treat symptoms of menopause rather than for disease prevention and therefore the risks and benefits of hormone replacement therapy in the general population differ from the women included in the WHI.
Post-study analysis showed that the age of hormone replacement initiation plays a major role in the risk of heart disease and breast cancer. Women who begin hormone replacement therapy 10 years after menopause have much greater risk than women who begin therapy less than 10 years after menopause. In the estrogen-only trial of WHI, women from 50-59 years taking estrogen had fewer heart attacks, deaths, and adverse events than women taking placebo while women from 70-79 years taking estrogen has more heart attacks, death, and adverse events than women taking placebo.
Women in the WHI estrogen-only trial had a mean duration of therapy of 6 years. Women in the estrogen-progestin trial had an even shorter duration of hormone therapy. The risks and benefits of long-term hormone replacement therapy are unknown.
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]
