Women’s Health Initiative Commentary

Mary K. Beard, MD, FACOG
Department of Obstetrics and Gynecology
Adjunct Clinical Professor, University of Utah

Dr. Goldman is not alone in raising the various concerns presented in his article. The Women’s Health Initiative (WHI) was designed to answer many of the issues regarding the benefits and risks of hormone therapy (HRT). However, the entry criteria did not reflect standard practice in the clinical selection of women for HRT. With 66% of the women over age 60 and first time users of hormone therapy, the study was biased against beneficial effects because of the increased prominence of age dependent cardiovascular, thromboembolic, and neoplastic events. Obesity, diabetes, smoking, and hypertension were present in a significant number of participants and there was a lack of socioeconomic breakdown, another important factor in cardiovascular disease. This all brings into question the validity of the WHI as a primary prevention trial. In addition, the high attrition rate from about 8,000 to 1,500 participants potentially modified the results. The adverse outcome rate compared with the underlying diseases of the participants needs to be evaluated. The WHI did demonstrate the ability of HRT to decrease the risk of colon cancer and prevent spine, hip and total fractures in a population of older, nonosteoporotic, postmenopausal women.

The discontinuation of the estrogen/progestin arm of the WHI trial has lead to a flurry of news media blitz and articles being published, which has created fear of all estrogens. As a result, patients have been abruptly stopping their hormone therapy, believing that all hormones are unsafe. And yet there is not universal agreement in the medical community that this is the appropriate action. Some experts around the world such as Dr. Malcolm Whitehead from the UK question if it “Is appropriate to withdraw treatment because the regulators say you can not use hormone therapy long term?”(1). In many instances, patients no longer know whom to believe. In some cases patients were told to stop their hormone therapy and have become afraid of all prescription medications. Many are turning to nontraditional medicine to relieve symptoms. However, without hormone therapy many women will suffer rapid loss of bone. Dr. Goldman is correct that osteoporosis is already under diagnosed and under treated. Without public understanding of the effects of estrogen discontinuation on bone density and osteoporosis, this will likely become an even bigger problem. The WHI has not adequately evaluated the risk of osteoporosis especially in the wake of so many women discontinuing hormone therapy.

The perimenopausal years result in bone mass loss that can begin 2-3 years prior to the last menses. Recker, et. al. reported perimenopausal bone loss as high as 10% in the spine, 5.3% in the femoral neck and 7.7% in the total body (2). The relationship between low estrogen, postmenopausal bone loss, and increased fracture risk is well established. With this knowledge, women need to be started on bone protection early. Since hormone therapy confers protection at all skeletal sites, the optimal approach is early treatment and consistent follow up on patient adherence to the treatment regimen during the critical period of accelerated bone loss that starts at the onset of menopause and continues for several years thereafter.

Many epidemiological studies indicate that hormone therapy confers protection against bone loss and fractures for as long as 10 or more years of treatment. Early intervention studies coordinated in randomized trials with hormone therapy for the prevention of postmenopausal osteoporosis have been completed in Finland and Denmark. These studies support the early initiation of hormone therapy for the effective prevention of postmenopausal osteoporosis.

Various treatment options are available including bisphosphonates, calcitonin, selective estrogen receptor modulators, parathyroid hormone and hormone therapy. However, hormone therapy still remains one of the best options for the prevention of osteoporosis and is also the most cost effective. It should always be remembered that hormone therapy might not be appropriate for some women. Lower doses and various routes of delivery as well as different preparations may need to be considered. The risk benefit profile should be evaluated sensibly with further research directed at accurately identifying the at-risk population.

The American College of Obstetricians and Gynecologists recommends prescribing HRT for as short a time as possible and at the lowest effective dose. Each patient is unique and must be treated individually. In some women symptoms last five years and, others, 40 years. Patients, after being informed of the benefits and risks, should be allowed to decide the duration of therapy. If estrogen is not prescribed or is discontinued, close monitoring of bone density and other interventions for the prevention or treatment of osteoporosis should be recommended.

References:

1. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial. JAMA 2002;288:321-33

2. Freedman L, Anderson G, Kipnis V, et al. Approaches to Monitoring the Results of the Long-term Disease Prevention Trials: Examples from the Women’s Health Initiative. Controlled Clinical Trials 1996;17:509-22

3. The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative Clinical Trial and Observational Study. Controlled Clinical Trials 1998;19:61-109

4. NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk, Lack of Overall Benefit. NIH News Release, July 9, 2002; pp1-4.

5. Shumaker SA, Legault C, Rapp SR, et al. Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women’s Health Initiative Memory Study: A Randomized Controlled Trial. JAMA 2003;289: 2651-62.

6. Goodson WH. Risks of Postmenopausal Hormone Replacement. JAMA 2002;288:2819-24.

7. Greenlee TR, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin. 2000;50:7-33.

8. Manson JE, Hsia J, Johnson KC et al. Estrogen plus Progestin and the Risk of Coronary Heart Disease. N Engl J Med 2003;349:523-34.

9. Hodis HN, Mack WJ, Azen SP, et al. Hormone Therapy and the Progression of Coronary-Artery Atherosclerosis in Postmenopausal Women. N Engl J Med 2003;535-45.

10. Herrington DM, Howard TD. From Presumed Benefit to Potential Harm. N Engl J Med 2003;349:5519-21.

11. Hays J, Ockene JK, Brunner RL, et al. Effects of Estrogen plus Progestin on Health-Related Quality of Life. N Engl J Med 2003;348:1839-54.

12. Zhange Y, McAlindon TE, Hannan MT, et al. Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study. Arthritis Rheum 1998;41:1867-73.

13. Wluka AE, Davis SR, Bailey M, et al. Users of estrogen replacement therapy have more knee cartilage than non-users. Ann Rheum Dis 2001;60:332-6.

14. Osteoporosis Fast Fact, National Osteoporosis Foundation. 2000

15. National Institutes of Heart, Lung and Blood Institute. Health Heart Handbook for Women. 2000.

16. Statistical Information on Women and Women’s Health. US Department of Health and Human Services. 2000.

17. Hormone replacement therapy in the post-Women’s Health Initiative era. A report of a meeting held in Funchal Madeira Feb. 24-25, 2003. Climacteric. J of the International Menopause Society 2003;6, S1.

18. Recker R, Lappe J, Davies K, et al. Characterization of perimenopausal bone loss: a prospective study. J Bone Miner Res 2000;15:1965-73.

Last modified: December 17, 2012