Statement of the American Society for Bone and Mineral Research regarding the results of the Women's Health Initiative Hormone Therapy (HT) Trial.
Revised September 2005
The combination hormone therapy (HT) arm of the Women's Health Initiative (WHI) was stopped in July 2002 on the advice of the Data and Safety Monitoring Board because of an increased risk of breast cancer and an unacceptable rate of unfavorable outcomes (global index). Although combination hormone therapy produced a significant reduction in the risk of hip fractures, vertebral fractures, and other osteoporotic fractures, as well as a reduction in the risk of colorectal cancer, these favorable effects were more than offset by increases in the rates of breast cancer, myocardial infarction, stroke, and venous thromboembolic events. The absolute increase in rates for these events with HT was low: for each end point, fewer than 10 cases per 10,000 person-years; overall, 19 more events caused than events saved per 10,000 person-years. In addition, subsequent data analyses showed a 2-fold increased risk of dementia in HT-treated women older than 65 years.
The estrogen-only arm of WHI in postmenopausal women who had had hysterectomy was stopped early after 6.8 years because it became apparent that the risk of stroke was increased, and there was no protection against coronary disease. In this randomized, placebo-controlled trial, conjugated estrogen did protect against fractures, including a 39% reduction in hip fractures, and was not associated with an increase in breast cancer risk. But overall risks and benefits were essentially neutral. The excess risk according to the global index was insignificant with an absolute risk of 2 events per 10,000 person-years
The potential benefits of estrogen or combination hormone therapy in terms of relief of peri-menopausal symptoms are well established and risks of coronary heart disease and breast cancer are generally very small in early post-menopausal women. Women enrolled in the WHI were 50 to 79 years at baseline; thus, these data do not apply to younger women who develop premature menopause. To relieve menopausal symptoms, short-term use at the lowest doses should be used. Urogenital symptoms can be effectively treated in some women with administration of vaginal estrogen pills, rings or creams. Before estrogen or combination hormone therapy is instituted, women should be informed about the potential risks.
For women without menopausal symptoms, although the risks to an individual are small, benefits are even smaller, and so estrogen therapy alone or in combination with a progestin should not be used for prevention of chronic disease.
Women who have osteoporosis or are at risk may be managed with other agents. Management decisions will be enhanced by bone density testing and assessment of risk factors for fracture.
There are now answers to the questions posed in the 2002 ASBMR Statement Regarding the Results of the Women's Health Initiative HRT Trial:
1. Is there a subset of women for whom HT might be appropriate for its skeletal benefits? The answer appears to be "no," at least for older postmenopausal women. For combination hormone therapy, women at higher risk of fracture, who stand to benefit the most in this regard, still had an unfavorable global index, meaning that the protection against fractures is not enough to offset the negative effects on other body systems. Alternatives to hormone therapy, such as bisphosphonates, raloxifene, calcitonin, or teriparatide, should be used for treatment of postmenopausal osteoporosis. It is possible that the overall risk-benefit ratio may be quite different in a younger peri- or early postmenopausal women, as suggested by subgroup analyses by age groups in the estrogen only arm of the WHI trial. However, no conclusive statements regarding that possibility can be made because the WHI was not designed to evaluate the risk-benefit ratio of hormone therapy in peri- or early postmenopausal women.
2. Is the risk/benefit ratio different for other HT regimens, or for estrogen given without a progestin? Whereas the overall risk/benefit profile of estrogen used in combination with medroxyprogestrone acetate was unfavorable, the use of estrogen only was neutral However, the estrogen only arm was carried out in women who had had a hysterectomy with about 40% having had a bilateral oophorectomy. There are no other large studies that have looked at estrogen in other forms, doses, or routes of administration, and the overall risk/benefit ratio for these formulations is therefore unknown.
3. What is the risk/benefit ratio of HT for symptom relief and quality of life? This was addressed to some degree in WHI, with the conclusion that there was no benefit in quality of life. The subjects in WHI may not have been the best for this assessment, and the tools were probably not sensitive enough. Estrogen or HT for relief of vasomotor symptoms is a viable option for symptom relief in recently menopausal women. Women who take estrogen or HT for symptom relief should experience skeletal benefits, but these benefits will probably not extend beyond the period of use of HT.
4. Is the risk benefit ratio any different for women who have been on HT for several years? Although more women in the Estrogen only arm had used hormone therapy and had a longer lifetime exposure to HT than women enrolled in the Estrogen and Progestin study of the WHI, there are no data that show clear benefit of long-term use. While women in the estrogen only arm showed no increased risk of heart disease or breast cancer in 6.8 years, there was no benefit in prevention of disease. Moreover, there are differences in women enrolled in the two trials including a history of hysterectomies with or without oophorectomies in the estrogen only arm and use of progestin in the Estrogen plus Progestin study. Women who are currently taking estrogen or HT should seek advice from their physician.
A. If estrogen/HT was started for prevention or treatment of osteoporosis, consideration should be given to changing to another agent for prevention or treatment of osteoporosis.
B. If estrogen/HT was started with hopes of a cardiovascular benefit, or for some other reason that is not supported by current medical evidence, or for reasons that are not clear, therapy should be stopped.
C. Asymptomatic postmenopausal women who have osteoporosis or are at risk should strongly consider options other than estrogen. Estrogen is not now nor has it been approved for the treatment of osteoporosis. However, physicians may find "off label" use of estrogen or combination hormone therapy to be appropriate in specific individual circumstances.
D. If estrogen/HT was started during peri- or early postmenopausal symptoms, the decision to continue such treatment has to be individualized. Estrogen/HT is the most efficacious therapy for vasomotor symptoms, and in the event of continued HT/ERT adequate medical supervision, surveillance and periodic re-evaluation are indicated. The overall risk benefit ratio in this age group may be different from that noted in older postmenopausal women.
Women discontinuing estrogen should be considered for bone density testing according to established indications (healthy women should be screened at age 65; higher-risk postmenopausal women should be tested earlier).