10 Years after the WHI: Should This Study Guide Our Thinking About Menopausal Hormone Therapy?

Abstract & Commentary

By Jeffrey T. Jensen, MD, MPH

Dr. Jensen is Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR

This article originally appeared in the August issue of OB/GYN Clinical Alert. Dr. Jensen receives research support from, is a consultant to, and serves on the speakers bureau of Bayer Healthcare and Merck; he also receives research support from Abbott Pharmaceuticals and Medicines360.

Synopsis: The U.S. Preventive Services Task Force updated its systematic review of menopausal hormone therapy. The findings, heavily influenced by the Women’s Health Initiative results, do not support the use of hormone replacement therapy to prevent chronic conditions.

Source: Nelson HD, et al. Menopausal hormone therapy for the primary prevention of chronic conditions: A systematic review to update the U.S. Preventive Services Task Force Recommendations. Ann Intern Med 2012 [Epub ahead of print].

TO PROVIDE GUIDANCE TO CLINICIANS ON THE USE OF HORmone replacement therapy, the authors conducted a systematic review of the randomized, placebo-controlled trials of menopausal hormone therapy published in English since 2002 that assessed primary prevention of chronic conditions. They used several databases and reference lists of published papers to find manuscripts that met these criteria. Investigators extracted data on participants, study design, analysis, follow-up, and results, and the overall quality of each study was rated by two investigators who worked independently and according to established criteria. Of 4524 abstracts identified from searches, 51 full-text articles that included results from nine randomized trials met the inclusion criteria. However, only the Women’s Health Initiative (WHI) main and follow-up studies were considered to meet the criteria for inclusion, as they were designed and powered to focus on the outcomes of chronic disease. Therefore, the WHI findings provided the basis for the results and recommendations of the manuscript.

The estrogen plus progestin (E/P) arm of WHI showed reduced fractures (46 fewer per 10,000 woman-years), but increased invasive breast cancer (eight more per 10,000 woman-years), stroke (nine more per 10,000 woman-years), deep venous thrombosis (12 more per 10,000 woman-years), pulmonary embolism (nine more per 10,000 woman-years), lung cancer death (five more per 10,000 woman-years), gallbladder disease (20 more per 10,000 woman-years), dementia (22 more per 10,000 woman-years), and urinary incontinence (872 more per 10,000 woman-years). Estrogen-only therapy reduced fractures (56 fewer per 10,000 woman-years), invasive breast cancer incidence (8 fewer per 10,000 woman-years), and death (two fewer per 10,000 woman-years), but increased stroke (11 more per 10,000 woman-years), deep venous thrombosis (seven more per 10,000 woman-years), gallbladder disease (33 more per 10,000 woman-years), and urinary incontinence (1271 more per 10,000 woman-years). In their review, the authors state that outcomes did not consistently differ by age or comorbid conditions. The U.S. Preventive Services Task Force (USPSTF) recommendations conclude that while both estrogen plus progestin and estrogen only hormone therapy regimens decrease the risk for fractures, both increase the risk for stroke, thromboembolic events, gallbladder disease, and urinary incontinence. While estrogen plus progestin also increases the risk for breast cancer and dementia, estrogen alone decreases the risk for breast cancer.

Commentary

If these recommendations sound familiar, it is because they are not changed from those published by the USPSTF in 2002 (after the initial combined estrogen plus progestin WHI study) and in 2005 (after the estrogen only WHI study). So much has happened in the last 10 years, but one thing that has not occurred is another large-scale, randomized trial the size of the WHI. With budget cutbacks at the National Institutes of Health, it is very unlikely that we will ever see this study repeated, so we need to live with the limitations and strengths of the study.

Given that the USPSTF focuses on the highest quality of evidence, it is not surprising that the results of a large randomized, controlled trial (RCT) like the WHI influence these recommendations. If we knew nothing else about the biology of hormonal therapy, it would make sense to follow these guidelines. Fortunately, considerable progress over the last 10 years has helped us place the WHI in perspective.

Without considering this background, the simple repetition of the key findings of the WHI results becomes misleading. This is a particular problem because the opinions of the USPSTF are so influential for our primary care colleagues and for policy makers. The present USPSTF report regurgitates the main findings without providing any real recommendations. On a positive side, the paper reports the attributable risk (of benefits and adverse events) rather than relative risks. However, the conclusions offered simply replay these findings without providing any context as to which women might be at greater or lesser risk, and whether a health benefit might outweigh a particular risk for an individual woman. There is no clear recommendation for postmenopausal women to either use therapy or avoid it. What does it mean that estrogen-only therapy is associated with a reduction in breast cancer risk and overall mortality? So much for guidance.

Our current understanding of hormone replacement therapy (HRT) is that thrombosis is the principle risk, not breast cancer.1 Thrombosis is related to estrogen-induced changes in hepatic globulins. Current research supports the use of non-oral routes of estrogens, and the use of estradiol rather than ethinyl estradiol to avoid the first pass effect of oral therapy on the liver.2 I recommend estradiol in a patch, gel, or vaginal ring to my patients and measure estradiol levels to ensure that they are in the 40-100 pg/mL range. Since WHI evaluated only oral conjugated estrogens, it provides no guidance on this important question or route of therapy. Data from the ESTHER study showed no increase in the risk of venous thrombosis in users of transdermal estradiol compared to non-users, but an increase in risk in women using oral products.3 Although not an RCT, this evidence is compelling and supports the supposition that avoiding the first pass effect might be beneficial.

We also know that timing of initiation of therapy matters. Contrary to the discussion of the present USPSTF report that repeated that the main effects of WHI applied to all subgroups, the follow-up reanalysis of the E/P treatment group actually documented a nonsignificant trend toward protection (hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.5-1.5) in women less than 10 years postmenopausal in contrast with the elevated risk (HR 1.71; 95% CI 1.1-2.5) observed in women starting therapy more than 20 years after menopause.4 The general health and cardiovascular risk factors of an individual woman should be taken into account during the discussion regarding initiation of HRT.

What about breast cancer? The results of the combined E/P and estrogen only WHI studies differ in several clinically important outcomes. The trend toward a reduction in risk of invasive breast cancer in the estrogen-only arm has persisted in the most recent analysis of results from this study.5 This is in marked contrast to the results seen with E/P, so medroxyprogesterone acetate must have a negative impact on breast health. The safest choice for systemic progestogen therapy is probably oral micronized progesterone, but we still don’t know enough about dose to guarantee endometrial protection.

So the main thing to know about this study is that you can ignore it. There is nothing new in this paper, and you should continue to provide a balanced discussion of the potential benefits and risks of postmenopausal hormone therapy.

References

1. Harman SM. Estrogen replacement in menopausal women: Recent and current prospective studies, the WHI and the KEEPS. Gend Med 2006;3:254-269. PMID:17582367.

2. Sandset PM, et al. Mechanisms of thrombosis related to hormone therapy. Thromb Res 2009;123(Suppl 2):S70-73. PMID:19217481.

3. Canonico M, et al. Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation 2007;115:840-845. PMID:17309934.

4. Manson JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356:2591-2602. PMID:17582069.

5. LaCroix AZ, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: A randomized controlled trial. JAMA 2011;305:1305-1314. PMID:21467283.