03: Breaking Down the WHI Hormone Therapy Trials
EP. 03
Ever since the first Women’s Health Initiative (WHI) findings were announced in 2002, women have been led to believe that hormone replacement therapy (HRT) is unsafe. The premature halt of estrogen-progestin therapy due to safety concerns resulted in a significant decline in HRT use, leaving many women to needlessly abandon a treatment that offered symptomatic relief from severe menopausal symptoms.
In today's episode, we're diving deep into the WHI hormone therapy trials. We'll explore the key questions the trials aimed to answer, delve into the study's design, and dissect the findings from both the estrogen and progesterone arm and the estrogen-only arm. Additionally, we'll examine the conclusions drawn from the study, recent revisions to those conclusions, and emphasize the urgent need for further research in this area of women's health.
Join me as we unravel the complexities of the WHI study and uncover the truths behind hormone replacement therapy.
Listen to the full episode:
Inside the Women's Health Initiative: Research Objectives and Structure
The Women's Health Initiative (WHI), is a significant long-term study aimed at understanding and promoting the health of postmenopausal women. The study iInitiated in 1991 and the WHI is sponsored by the National Heart, Lung, and Blood Institute (NHLBI), a part of the National Institutes of Health (NIH). This extensive study comprises three main components: clinical trials, observational studies, and community prevention trials.
The clinical trials, which we'll focus on here, are particularly intriguing. Over 68,000 postmenopausal women aged 50 to 79 were enrolled, making it one of the largest studies of its kind. Notably, participants were randomly assigned to one of three groups: hormone therapy, dietary modification, or calcium and vitamin D supplementation. Randomized controlled trials (RCTs) like these are considered the gold standard in research methodology, as they provide rigorous scientific evidence.
In the clinical trials, there was the hormone trial, consisting of two distinct studies: one evaluating estrogen plus progesterone for women with an intact uterus, and another examining estrogen alone for women without a uterus. The goal was to investigate the effects of hormone therapy on various health outcomes in postmenopausal women. Additionally, a diet modification trial explored the impact of a low-fat, high-fiber diet on reducing the risk of breast cancer, colorectal cancer, and heart disease. Similarly, a calcium and vitamin D supplementation trial aimed to evaluate their efficacy in preventing osteoporosis-related fractures and colorectal cancer.
Exploring the Hormone Trial in the Women's Health Initiative
The study, initiated when participants were around 63 years old on average, aimed to assess how hormone therapy affected women's health. However, some argue that the study began too late, considering that women's hormone levels start declining in their mid-30s to 40s.
Participants received high-dose hormones, including conjugated equine estrogen (CEE) and Medroxyprogesterone (MPA), which are now seen as outdated compared to newer, FDA-approved bioidentical hormone preparations. The trial mainly focused on two outcomes: coronary heart disease and invasive breast cancer, along with a broader assessment known as the global index, which considered additional factors like stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fractures, and mortality.
Initially set to continue until 2026, the trial was stopped in 2002 due to concerning findings. Analysis showed an increased risk of invasive breast cancer and other adverse outcomes, leading to the discontinuation of hormone replacement therapy. Subsequent analyses based on age groups (50-59, 60-69, and 70-79) provided further insights.
Age Stratification Reveals Surprising Trends in WHI Study Outcomes
In the initial analysis of the WHI study, all women, regardless of age, were grouped together, leading to a generalized understanding of the outcomes. However, it wasn't until the trial was stopped that researchers conducted a more detailed analysis by stratifying the data based on age groups: 50-59, 60-69, and 70-79.
Some intriguing patterns emerged from the stratified analysis. For instance, in the estrogen plus progesterone trial, while there was an initial increased risk of coronary heart disease in the first year, this risk decreased thereafter. Notably, there was no change in heart attack risk for women aged 50-59 or 60-69, but an increased risk was observed for those aged 70-79. Additionally, stroke risk escalated across all age groups, along with increased risks of blood clots and invasive breast cancer.
However, amidst these concerning trends, some positive outcomes surfaced. The stratified analysis revealed a decreased risk of endometrial cancer, colorectal cancer, and hip fractures. Furthermore, all-cause mortality decreased notably in the 50-59 age group, with no significant change in the 60-69 group. Surprisingly, the estrogen-only arm of the study showed a decrease in coronary heart disease risk for women aged 50-59, with no significant change in older age groups.
Most strikingly, the estrogen-only therapy was associated with a decreased risk of invasive breast cancer across all age categories. Additionally, a decrease in hip fracture risk was observed across the board in the estrogen-only arm, accompanied by a reduced risk of all-cause mortality, except for a slightly increased risk in the 70-79 age group, the cause of which remains unclear.
Additionally, self-reported data indicated a decrease in diabetes incidence across both treatment groups. As an endocrinologist, this is significant to me because diabetes itself increases your risk of having a stroke and heart disease if your diabetes is poorly controlled.
While diabetes risk decreased, there was an increased incidence of gallbladder disease, which was not surprising considering the known associations. However, the higher incidence of urinary incontinence was confusing and warrants further investigation. Reductions in hot flashes, sleep disturbances, and joint pain were also observed. Interestingly, while quality of life improved in the estrogen plus progesterone group, it worsened in the estrogen-only group. These self-reported observations offer valuable insights into patient experiences and outcomes beyond clinical metrics, albeit with some limitations in accuracy compared to objective measures.
Unraveling Misconceptions and Moving Forward
Reflecting on the Women's Health Initiative (WHI), particularly its hormone trial, it's clear how initial conclusions triggered widespread concern among both patients and healthcare providers. The study suggested that using estrogen plus progesterone after menopause could increase the risk of heart disease, stroke, blood clots, breast cancer, and dementia. This led many people, including doctors, to stop using hormone therapy altogether.
But as time went on and more analysis was done, the picture became more complicated. While it seemed like estrogen-only therapy might help younger women who had their uterus removed, there were still worries about higher risks of stroke and blood clots. Overall, the advice became more cautious, saying that hormone therapy shouldn't be used to prevent heart disease or lower cholesterol in postmenopausal women. However, it could still be an option for easing severe menopause symptoms, as long as it was done carefully.
A later review of the WHI findings by the Journal of the American Medical Association provided a more balanced view. It said that while hormone therapy might not prevent heart disease or other chronic conditions in postmenopausal women, it could still help with menopause symptoms in some cases.
This whole story shows how important it is to look at medical research carefully and not jump to conclusions based on initial headlines. It also highlights the need for more research, especially focusing on women going through perimenopause and their metabolic health.
In the end, the WHI study reminds us to think critically about medical information and to keep working towards better understanding and care for women's health at all stages of life.
Finding a NAMS Certified Menopause Practitioner (NCMP)
The North American Menopause Society offers a search tool to find a NCMP in your area.