Prior to the WHI, observational studies suggested that postmenopausal hormone therapy was associated with a decreased risk of coronary heart disease. Other research findings indicated that hormone therapy was also associated with a decreased risk of osteoporosis and increased bone density, although the effects of hormone therapy on actual fracture incidence had not been determined. The WHI Hormone Therapy Trials (HT) were designed to test the effects of postmenopausal hormone therapy on women’s risk for coronary heart disease (primary analyses) and on hip and other fractures and breast cancer (secondary analyses). The effects of hormone therapy on endometrial cancer was also evaluated in women with a uterus. Previous research on hormone therapy and disease outcomes, as background to the WHI HT, are reviewed in the WHI Protocol.
In addition to the general Clinical Trial exclusion criteria, HT-specific eligibility criteria were focused on safety (e.g., no history of hypertriglyceridemia or endometrial cancer, normal mammogram) and adherence. All participants who were eligible for and interested in the HT were dispensed a 28-day supply of placebo study pills for an enrollment (run-in) trial, which could be repeated once. An adherence of 80% or greater during the enrollment period was required for eligibility.
The HT consisted of two separate clinical trials in postmenopausal women ages 50 to 79 years at baseline—a trial of combined estrogen and progestin (Estrogen plus Progestin or E+P) in women who had an intact uterus at baseline (n=16,608) and a trial of estrogen (Estrogen Alone or E-Alone) in women who had a prior hysterectomy at baseline (n=10,739). When the WHI began in 1993, women with a uterus were also randomized to unopposed estrogen or a placebo, but those participants assigned to active treatment were reassigned to combined estrogen plus progestin in early 1995. Baseline characteristics of participants in the E+P and E-Alone trials are available in the HT baseline monograph.
Following a WHI Data and Safety Monitoring Board (DSMB) review of the cumulative data to date, the E+P trial was stopped early in July 2002. The DSMB determined that combined estrogen plus progestin was associated with an increased risk of breast cancer, some increased risk of cardiovascular disease, and more harm than benefit overall (see main trial findings, below). The Estrogen-Alone trial was stopped early in March 2004, because an increased risk of stroke was found with no benefit for coronary heart disease (see main trial findings, below). The National Institutes of Health determined that follow-up for the remaining years would not change these overall findings and it would not be appropriate to expose healthy women to this risk in a prevention trial.
Participants with an intact uterus at baseline were randomized in a 1:1 fashion to one of two arms:
Combined hormone therapy, consisting of 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily (Prempro, Wyeth, Philadelphia, PA)
Daily placebo pill
Participants with a history of hysterectomy at baseline were randomized in a 1:1 fashion to one of two arms:
Unopposed estrogen therapy, consisting of 0.625 mg of conjugated equine estrogens daily (Premarin, Wyeth, Philadelphia, PA)
All HT participants were given an “HRT Handbook,” which was offered each time study pills were dispensed. This handbook was updated several times throughout the study to address recent WHI and other hormone findings. The handbook included HT-specific information about:
Safety (e.g., having annual mammograms, notifying clinic staff or health care providers about serious health changes)
Adherence (e.g., taking study pills daily, managing symptoms)
Retention (e.g., coming in for clinic visits)
HT participants were followed up six weeks after randomization to address management (e.g., symptoms and adherence) and safety issues and then semi-annually for health-related outcomes and management and safety issues. Clinic visits were required annually, during which additional physical and gynecological examination data were collected and reviewed for safety concerns. HT participants were also required to have annual mammograms, and study pills were not dispensed if a benign mammogram report had not been received in the previous 18 months. Follow-up data collected on HT participants can be found under Frequency of Data Collection.
If symptom or safety concerns (e.g., vaginal bleeding, breast changes) or adherence challenges were noted, these concerns were evaluated and addressed during participant contacts by trained clinicians and followed-up as appropriate.
Participants were advised on self-care strategies for managing symptoms. A detailed algorithm for managing vaginal bleeding in the E+P trial was developed and was included in the HT section of the staff procedures manual (below) and a consulting gynecologist’s handbook that included excerpts of study procedure and forms. Strict safety criteria were defined for unblinding a participant’s treatment arm, with only the clinic’s consulting gynecologist being unblinded, as necessary, to manage bleeding. Briefly, no intervention was required during the first 6 months after randomization if vaginal bleeding was equal to or lighter than a regular menstrual period. For heavier bleeding early on, or for bleeding after 6 months, algorithms focused on severity of bleeding, time since randomization, study arm, and endometrial pathology (of endometrial aspiration or transvaginal uterine ultrasound). Additional “open-label” estrogen or progestin, referral to a personal health care provider, or discontinuation of study pills were ordered based on these specific protocols, with re-evaluation in 6 months, as appropriate.
HT study pills were discontinued temporarily or permanently, without unblinding treatment arm, for participants who developed certain health conditions (e.g., breast cancer, endometrial cancer) or began taking certain prescription medications (e.g., hormone therapy, selective estrogen receptor modulators). Problems that may have affected continuation of study pills are described in the HT section of the staff procedures manual (below).
Stefanick M, Cochrane B, Hsia J, Barad D, Liu J, Johnson S. The WHI Postmenopausal Hormone Trials. Ann Epidemiol 2003;13:S78-S86.
The Writing Group for the WHI Investigators. Risks and benefits of estrogen plus progestin in healthy post-menopausal women: Principal results of the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-333.
The Women's Health Initiative Steering Committee. Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy. The Women's Health Initiative Randomized Controlled Trial. JAMA 2004;291:1701-1712.
About WHI section > Screening and Enrollment > Study Consent Forms
WHI Manuals: Volume 2, Section 5 - Hormone Therapy
WHI Overview section > Design and Protocol > WHI Timeline
WHI Overview section > Retention and Adherence > Adherence in the HT and CaD Trials.
Publications section > All published papers > HT
Participant update: Hormone Program Update - April 2004
Participant update: Actualización sobre el Programa de Hormonas - Abril de 2004
Participant update: What about Estrogen-Alone? * - May 2003
Participant update: Hormone Program Update * - June 2002
Participant update: Hormone Program Update * - 2001
Participant update: Hormone Program Update * - 2000
Participant update: DVT Update - September 1997