Women's Health Initiative
Encyclopedia
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 trial
s were designed and funded that address cardiovascular disease
, cancer
, and osteoporosis
.
, 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:
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. Hormone replacement therapy use declined in the U.S. and around the world, followed by a decline in breast cancer.
, 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:
A secondary endpoint was postmenopausal weight gain. Long term daily supplementation of calcium with vitamin D resulted in a small prevention of weight gain.
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.
External Links=
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(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 trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
s were designed and funded that address cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, and osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
.
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 estrogenEstrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
, specifically conjugated equine estrogen, plus progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
(Prempro, Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
) compared to placebo
Placebo-controlled studies
A Placebo-controlled study is a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect...
(the "WHI-E+P" trial), among healthy postmenopausal women.
This trial found that, compared with placebo, women receiving estrogen plus progestin experienced:
- increased risk of myocardial infarctionMyocardial infarctionMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
("heart attack") - increased risk of strokeStrokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
- increased risk of blood clots, including deep venous thrombosis (DVT) and pulmonary embolismPulmonary embolismPulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
(PE) - increased risk of breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
- decreased risk of colorectal cancerColorectal cancerColorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
- 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. Hormone replacement therapy use declined in the U.S. and around the world, followed by a decline in breast cancer.
Conjugated estrogen versus placebo
This trial studied estrogenEstrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
, specifically conjugated equine estrogen (Premarin
Premarin
Premarin is the commercial name for a compound cream of vaginally administered estrogens, consisting primarily of conjugated estrogens. Isolated from mares' urine , it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942...
, 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
Endometrial cancer
Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
posed by unopposed estrogen.
Major results of this study were that, compared with placebo, women receiving estrogen alone experienced:
- no difference in risk for myocardial infarctionMyocardial infarctionMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
- an increased risk of stroke
- an increased risk of blood clots
- an uncertain effect on breast cancer risk
- no difference in risk for colorectal cancerColorectal cancerColorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
- 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.
- 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.
A secondary endpoint was postmenopausal weight gain. Long term daily supplementation of calcium with vitamin D resulted in a small prevention of weight gain.
Non-intervention cohort
The non-interventional observational cohort study ("WHI-OS") observed 93,000 women drawn from the same national clinical coordinating centers (many epidemiologyEpidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
studies conducted within this observational component of the WHI).
The WHI Postmenopausal Hormone Therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
Trials were part of the effort to address the high risk of cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
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
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
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
Premarin
Premarin is the commercial name for a compound cream of vaginally administered estrogens, consisting primarily of conjugated estrogens. Isolated from mares' urine , it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942...
). 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
Medroxyprogesterone
Medroxyprogesterone is a pregnane that acts as a progestin. An acylated derivative, medroxyprogesterone 17-acetate is clinically used as a drug. Compared to MPA, MP is approximately 100 fold less potent as a progestin...
, 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
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
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.External Links=