Women's Health Initiative
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 trial found that, compared with placebo, women receiving estrogen plus progestin experienced:
- 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. Hormone replacement therapy use declined in the U.S. and around the world, followed by a decline in breast cancer.
Conjugated estrogen versus placebo 
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:
- 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.
- 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 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.
The WHI trial was limited by low adherence, high attrition, inadequate power to detect risks for some outcomes, and evaluation of few regimens. Subsequent to publication of the WHI, controversy arose regarding the applicability of its findings to women just entering menopause. To be properly double blinded, the study required that women not be perimenopausal or have symptoms of menopause. As the average age of menopause is 51, this resulted in an older study population, with an average age of 63. Only 3.5% of the women were 50–54 years of age, the time when women usually decide whether to initiate hormonal replacement therapy. Most fundamentally, the WHI did not address the major indication for MHT use, relief of symptoms. In a more recent expert consensus statement from The Endocrine Society, evidence from the WHI trial was weighted less than that of a randomized controlled trial according to the GRADE system criteria because of mitigating factors: large dropout rate; lack of adequate representation of applicable group of women (i.e. those initiating therapy at the time of menopause); and modifying influences from prior hormone use. The double blinding limited validity of study results due to its effects on patient exclusion criteria. The dominant majority of participants were Caucasian, and tended to be slightly overweight and former smokers, with the necessary health risks for which these demographics predispose. 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.
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.
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 those between 70-79 years of age taking estrogen had more heart attacks, death, and adverse events than those on 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.
Limitations of dietary analysis 
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.
Inconsistency of cardiovascular risk results over time 
The recommendations of the WHI varied in their publications over time, becoming less assertive as the study developed. The initial publication stated:
In addition, the substantial risks for cardiovacsular disease and breast cancer must be weighed against the benefit for fracture in selecting from the available agents to prevent osteoporosis.—Women's Health Initiative, 2002
Following this, they closed the combined estrogen-progesterone therapy arm due to perceived health risks of hormonal therapy. This was followed by a publication the following year, in which they wrote:
In the interim, women with indications for treatment, such as menopausal symptoms, need to consider with their clinicians the suggestion of a slight overall increase in the risk of CHD, and information on the risks of other outcomes in making decisions about the use of estrogen plus progestin therapy.—Women's Health Initiative, 2003
The strength of their recommendation completely attenuated in a 2007 publication:
The number of cardiovascular events increased with increasing age, but there was no statistically significant additional effect of hormone therapy for any outcome in the combined trials.—Women's Health Initiative, 2007
The authors finally published a complete reversal in 2008:
Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for statistical significance. A similar nonsignificant trend was observed for total mortality.—Rossouw et al, JAMA 2007 
The improving prognosis of their recommendations regarding cardiovascular risk have been a significant criticism in peer-reviewed medical literature.
- "Questions and Answers About WHI Postmenopausal Hormone Therapy Trials, NHLBI, WHI". 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.
- 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.
- 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.
- Nelson, H. D.; Walker, M.; Zakher, B.; Mitchell, J. (2012). "Menopausal hormone therapy for the primary prevention of chronic conditions: A systematic review to update the U.S. Preventive Services Task Force recommendations". Annals of internal medicine 157 (2): 104–113. doi:10.7326/0003-4819-157-2-201207170-00466. PMID 22786830.
- Santen, RJ; Utian, WH (2010). "Executive Summary: Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement". J Clin Endocrinol Metab. 95 S1–S66 (Supplement 1). Retrieved Feb 7, 2013.
- "Low-Fat Diet Not a Cure-All: Nutrition Source, Harvard School of Public Health". Retrieved 2008-03-28.
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- 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.
- Rossouw, J. E.; Prentice, R. L.; Manson, J. E.; Wu, L.; Barad, D.; Barnabei, V. M.; Ko, M.; Lacroix, A. Z. et al. (2007). "Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause". JAMA: the Journal of the American Medical Association 297 (13): 1465–1477. doi:10.1001/jama.297.13.1465. PMID 17405972.
- 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.