Disputing the Original Women's Health Initiative (WHI) Research Findings

Conducted from 1991 to 2005, the Women’s Health Initiative (WHI) study took an in-depth look at changes in women’s health as they age. As the largest preventative health study for women ever launched in the United States, its size and breadth opened the door for research into postmenopausal women’s health that had not been explored before.⁽¹⁾ 

Funded by the National Heart, Lung, and Blood Institute (NHLBI), the intent of the study was to develop preventative strategies against the top health conditions contributing to death, disability, and frailty among postmenopausal women, including heart disease, breast and colorectal cancer, and osteoporosis.⁽¹⁾ 

One section of the study focused on the effects of hormone replacement therapy (HRT), a treatment used by many women to increase declining levels of sex steroid hormones during the menopause transition. In the years since the WHI research findings were first released, experts have re-evaluated the study, recognizing its benefits as well as many of its limitations, which continue to influence women’s healthcare decisions about HRT. 

What is WHI?

The WHI is a long-term women’s health study that continues to this day, building on the work of the original research through Extension Studies.⁽²⁾ Between 1993 and 1998, over 160,000 postmenopausal women between the ages of 50 and 79 in the U.S. were enrolled in the study and followed for two decades.⁽³⁾ The research consisted of clinical trials, an observational study, and a community prevention study. 

The clinical trial segment of the study involved more than 68,000 participants and was broken down into the following three parts:⁽³⁾⁽⁴⁾ 

1. The HRT subtrial aimed to determine whether prolonged use of hormone therapy lowered rates of heart disease and bone fractures among postmenopausal women without putting them at risk for breast cancer. This article will primarily focus on the research findings from this portion of the study, which will be discussed below.

2. In the dietary modifications subtrial, researchers examined whether a low-fat diet rich in fruits, vegetables, and grains impacted women’s risk of heart disease, breast cancer, and colorectal cancer. Based on the findings, a low-fat diet was not recommended for the prevention of breast or colorectal cancer in menopausal women. However, further research into a potential link between a low-fat diet and reduced breast cancer mortality was encouraged.

3. The calcium and vitamin D supplementation subtrial looked at whether these supplements helped protect against fractures and colorectal cancer. Ultimately, supplementation was not recommended as an effective means to prevent fractures among menopausal women.

In the observational study, researchers analyzed data from clinic visits and participant self-reports to assess disease risk factors. The community prevention study zeroed in on identifying healthy behaviors and exploring how those behaviors could be developed into community-based public health interventions to protect those most affected.⁽⁴⁾ 

WHI Hormone Replacement Therapy Study

The HRT subtrial remains the most controversial part of the WHI study. Women with a uterus were given daily doses of estrogen in combination with progestin or a placebo, while women who had a hysterectomy received only estrogen therapy or a placebo.⁽⁵⁾ The study of the combination hormone treatment group was stopped early after research suggested that HRT could be harmful to postmenopausal women.⁽⁶⁾ The evidence showed an increased risk of breast cancer as well as higher rates of cardiovascular events, including the following:⁽⁷⁾ 

• Coronary heart disease

• Stroke

• Venous thromboembolism (VTE), or blood clots in the veins

The research had far-reaching global effects. Prior to the publication of the findings, approximately 40% of postmenopausal women in the U.S. were receiving hormone replacement therapy.⁽⁵⁾ In response to the results, HRT use among postmenopausal women dropped across the country by 46%.⁽⁷⁾

WHI Study Flaws

Over the years, experts have pointed out flaws in the WHI study, highlighting key points that likely influenced results.

1. The study used estrogen from horses. WHI used conjugated equine estrogens (CEE) extracted from the urine of pregnant horses, along with the progestin medication Prempro (medroxyprogesterone acetate).⁽⁵⁾ The CEE medication used in the study was a synthetic, nonbioidentical hormone therapy called Premarin.⁽⁸⁾ Unlike bioidentical hormones, synthetic hormones do not resemble the chemical structure of natural hormones made in the body. Humans produce three major types of estrogen (estradiol, estriol, and estrone), while Premarin contains a larger number of estrogens, many of which are only specific to horses.

2. Researchers did not randomize treatment groups based on baseline breast cancer risk. The incidence rates of breast cancer were unusually low in the placebo group, making the rates in the treatment group appear markedly high.⁽⁶⁾

3. The study did not factor in outside variables. While the initial findings showed a statistically significant association between HRT and the risk of breast cancer and coronary heart disease, these calculations did not adjust for confounding factors that could have skewed the results. In contrast, an adjusted analysis revealed that the risk measurements were not statistically significant.⁽⁷⁾

4. The study was not representative of all postmenopausal women. The postmenopause stage begins after menstruation has stopped for one year and continues for the rest of a woman's life. However, the majority of women in the WHI study were over the age of 60, leaving the research lacking data on early postmenopausal women.⁽⁷⁾

Benefits of the Women’s Health Initiative

The goal of the WHI was to collect data to help patients and their clinicians make informed healthcare decisions for women as they age. This landmark research project was the first long-term national health study focused on preventing heart disease, cancer, and osteoporosis in postmenopausal women. The WHI Extension Studies continue to shed light on issues related to women’s health. While the research remains concentrated on cardiovascular disease, cancers, and osteoporosis, the WHI Ancillary Studies also explore topics such as longevity, sleep apnea, and physical activity programs.⁽¹⁾

As a result of the study, a large number of women missed out on HRT treatments that could have benefited them during their menopausal years. However, the study organization has since expanded on the original findings. Although they do not recommend the therapy for disease prevention, further investigation has led the WHI to recognize HRT as the most effective treatment method for hot flashes and night sweats during menopause.⁽⁹⁾ 

Reanalysis of the study also showed that breast cancer risk dropped by 23%, and rates of breast cancer death declined by 40% in association with CEE treatment. However, the researchers noted that CEE treatment in combination with progestin did result in a slight increase in breast cancer incidence, though no increased risk of breast cancer death was observed.⁽⁹⁾ Further analysis also revealed that conjugated estrogen treatment may protect against heart disease, cancer, and all-cause mortality in menopausal women in their 50s, compared to women in the placebo group.⁽¹⁰⁾ 

Although misconceptions remain, these updates have helped ease women’s concerns around HRT. The risks identified in the original WHI study were associated with the use of synthetic hormones. Today, bioidentical HRT treatments can help relieve menopausal symptoms using hormones that are identical to those made in the body. Compounded bioidentical hormones also have the potential to be formulated in various dosage strengths and treatment forms, creating an opportunity for personalized dosing.