Investigators from the Women’s Health Initiative (WHI) Hormone Trials are reaffirming conclusions that hormone therapy is not recommended for the prevention of chronic disease, but may remain a reasonable option for the short-term management of menopausal symptoms for younger women. Investigators reached this conclusion after reviewing data from the trial and the extended post-trial follow up period.
“While the risk versus benefits profile for estrogen alone is positive for younger women, it’s important to note that these data only pertain to the short-term use of hormone therapy,” said Jacques Rossouw, M.D., chief of the Women’s Health Initiative Branch within the NHLBI’s Division of Cardiovascular Sciences. “There are no reliable data on the risks or benefits of long-term hormone therapy use for the prevention of chronic diseases.”
The update and overview, published today in the Journal of the American Medical Association (JAMA) presents the extended follow-up data for the first time and highlights findings related to conditions that affect quality of life. The paper also provides the most comprehensive look at the trials’ findings to date, with more detail on individual disease-specific outcomes, side-by-side comparisons of the two therapies (estrogen-alone and estrogen plus progestin), and a full breakdown of results by age and over time.
The WHI, which is sponsored by the National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI), followed women during a 13-year period.
“The combination of the six to seven years of intervention combined with the extended post-intervention follow-up make these hormone therapy medications among the best studied medications in medical history,” said Dr. JoAnn Manson, a principal investigator for the Women’s Health Initiative; chief of the division of preventive medicine at Brigham and Women’s Hospital; and professor of medicine at Harvard Medical School, Boston. “There are very few other treatments with this much information about the balance of benefits and risks over such a long period of time that include such a long post-intervention phase. The ultimate goal of this paper and the analysis is to help women and their health care providers make informed decisions.”
The Women’s Health Initiative studied 27,347 U.S. women ages 50-79 who enrolled in the Women’s Health Initiative Hormone Trials between 1993 and 1998. There were 16,608 women with an intact uterus in the trial of estrogen plus progestin and 10,739 without a uterus in the trial of estrogen-alone. Women with an intact uterus were enrolled in the estrogen plus progestin trial because of the need to add progestin to the therapy to protect against endometrial cancer.
Of those who participated in the original trial, 81 percent agreed to continue follow-up after the planned end of the trials. The WHI compared the rates of developing coronary heart disease including a heart attack (myocardial infarction), stroke, breast cancer, blood clots in the lungs, colorectal cancer, endometrial cancer, hip fracture, and death among women who were assigned to hormones versus women who were assigned to placebo study pills.
Those chronic diseases and deaths were combined in a global index to provide an overall measure of the balance of harm and benefit. The WHI researchers also studied several other important outcomes including dementia, other cancers, other fractures, diabetes, gallbladder disease, urinary incontinence, and quality-of-life outcomes including hot flashes, night sweats, sleep disturbances, mood and depression, breast tenderness, and joint pain.
Rates of overall illnesses (any one of the major illnesses studied) and death were 12 percent higher in women taking estrogen plus progestin than in women taking placebo pills during the trial. In absolute numbers, there were 20 more major illnesses or deaths per year for every 10,000 women taking estrogen plus progestin compared to the same number of women taking placebo. After women stopped taking the estrogen plus progestin therapy, there were no effects on overall illness and death. These results were the same in each age group but absolute numbers of additional illnesses and deaths were low in women aged 50-59 years (12 more for every 10,000 women per year). The results are based on a trial period of 5.6 years with an average of three years of actual hormone use and then no hormone use for eight or more years.
In women taking estrogen-alone, rates of overall illness and death were similar to those for placebo during and after the trial; however, these results differed importantly by age. For women taking estrogen alone in their 50s, there was a 16 percent reduced risk of overall illness and death. In absolute numbers, there were 19 fewer major illnesses or deaths per year for every 10,000 women in this age group compared to the same number taking placebo. Women in their 70s taking estrogen-alone had a 17 percent increased risk of overall illness and death with 51 more major illnesses or deaths per 10,000 women per year compared to placebo. This pattern of results was seen during the main trial of seven years with an average of four years of actual hormone use; with additional follow-up of seven or more years, the findings became more statistically significant.
The paper adds information about common conditions and diseases in postmenopausal women which affect their health and quality of life. In both regimens, diabetes risk is decreased by 14-19 percent, while risks of gallbladder disease and urinary incontinence are increased by 50-60 percent. Benefit for diabetes and risks of urinary incontinence and gallbladder disease lessened after the drugs were stopped.
“Decisions about hormone therapy are not easy, but these findings provide an evidence base for finding a way forward,” said Rossouw. “Hormone therapy affects many organ systems in the body and changes the risks of many diseases—some in good ways, others in bad ways. Depending on hysterectomy status, age, and other individual factors, the consequences can vary dramatically. The WHI emphasizes the need for women to talk about their risk factors with their doctors before making any decisions regarding hormone therapy.”
“The Women’s Health Initiative has been a transformative study that has had a dramatic effect on medical practice,” said Michael Lauer, M.D., director of NHLBI’s Division of Cardiovascular Sciences. “The in-depth analysis of intervention trial data and 13 years of cumulative data provided in this paper will help clinicians and women make informed decisions as to hormone therapy use.”