Key Findings From the Women's Health Initiative Study- July, 2002

Eligibility and enrollment

The WHI study recruited postmenopausal women in the 50-79 age range, and sought to be as inclusive as practical. The wide nature of the age range balanced the need to observe the effects of hormone therapy on younger women, while also attempting to capture physical and cognitive outcomes in older populations. In addition, a 20% minority enrollment rate was set for all components, to accurately represent the proportion of minorities within the study demographic (17% at the time of the 1990 U.S. Census). To achieve this, 10 of the 40 WHI clinical centers were designated as minority recruitment centers, with enhanced minority recruitment goals.

Eligibility and exclusion criteria also were defined, both study-wide and component-specific. Global inclusion criteria included postmenopausal women, between 50 and 79 years of age, who were willing and able to provide written consent, and who planned to reside in the study recruitment for a least three years after enrollment. Global exclusion criteria included medical conditions that would be predictive of a survival of less than three years, possessing characteristics or conditions that may diminish study adherence (e.g., substance abuse, mental illness, or cognitive impairment), or concurrent enrollment in another randomized controlled clinical trial.

For the CT, a partial factorial study design was utilized for the investigation of three overlapping interventions (dietary modification, hormone therapy, and calcium/vitamin D supplementation), as this would provide considerable cost efficiencies. Willing study-eligible women were asked to join either the hormone therapy (HT trial), the dietary modification (DM) trial, or both. After one year, willing and eligible CT participants were also asked to join the calcium/vitamin D trial (CaD).

Recruitment goals for the HT, DM, and CaD components of the CT were 27,500, 48,000, and 45,000, respectively, each obtained on the basis of calculations of statistical power with regard to the outcomes of interest for each component.

Participants who either did not qualify for or declined to participate in the CT were, if eligible and willing to consent, enrolled in the observational study (OS), which had an enrollment goal of 100,000 

 

Criticisms

 

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 therapy. Further analysis of WHI data, however, demonstrated that there is no gained preventive benefit in starting hormone therapy soon after menopause.

Most fundamentally, the WHI did not address the major indication for MHT use, relief of symptoms. On the other hand, the stated goal of the HT component was to test the long-term cardiovascular-protective effects (rather than treatment of menopausal symptoms) of HT in postmenopausal women, which had been supported by previous observational studies in terms of how it reduces atherosclerotic diseases by lowering serum lipid levels and promoting vasodilation. In an 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. However, the editor of one of the journals which published the results of the WHI called it a "landmark" study. 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 therapy to treat symptoms of menopause rather than for disease prevention and therefore the risks and benefits of hormone therapy in the general population differ from the women included in the WHI. Despite these concerns, the original findings of the WHI trial have been accepted by reputable journals, and have withstood the scrutiny of subsequent reanalysis of the study data.

OS component findings

The WHI OS has and continues to yield many findings and new hypotheses, a small sampling of which are highlighted below:

  • A decrease in invasive and ductal breast cancer incidences with decreasing estrogen/progestin combination therapy usage among the OS cohort, which served to corroborate the controlled HT CT trial findings. Other cancer surveillance studies have noted the same trend.

  • Identification of putative molecular markers which may predispose (and/or aid early detection) certain populations of women to diabetes and breast cancer.

  • Recognition that postmenopausal women are less active than they were during their pre-menopausal years, suggesting a possible benefit for interventions at or around peri-menopause. Furthermore, this decrease in activity (e.g., prolonged sedentary activity) can lead to an increased CVD risk.

  • A correlation between laxative use and an increased risk of falls, for both extrinsic and intrinsic reasons.

  • Identification of a positive correlation between active smoking or extensive exposure to second-hand smoke and an increased risk of breast cancer.

  • Identification of a potential positive relationship between alcohol use and the risk of developing certain types of hormone-responsive breast cancers.

  • An inverse correlation between whole grain consumption and type-2 diabetes, which is in agreement with previous studies; however, this study found the benefit of whole grain consumption to be lost with any history of smoking.

  • Insomnia, in combination with a long- (≥10 hours) or short-duration (≤5 hours) sleep pattern, can substantially augment the risk of CVD and CHD.

  • A combined analysis of the OS and CT cohorts found no convincing evidence for the influence of multivitamin supplement usage on common cancers, CVD, or total mortality.