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.
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 plus
progestin (Prempro, Wyeth) compared to
placebo (the "WHI-E+P" trial),
among healthy postmenopausal women.
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 on placebo. Hormone replacement therapy
use declined in the U.S. and around the world, followed by a
decline in breast cancer.
Conjugated estrogen versus placebo
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.
Calcium and vitamin D versus placebo
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
[99343]:
- CRC endpoint
- Fracture endpoint
Non-intervention cohort
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.
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) as well as external (a
group of post menopausal women is not generalizable to all women).
Finally, the mechanism of disease of developing breast cancer may
have a significantly longer time course than the duration of the
study, and intervention may have been most effective prior to
menopause.
Footnotes
References
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