Be Careful of What You Wish For: Putting the WHI Estrogen/progestin and HERS II Trials in Perspective

John F. Randolph, Jr, MD



We have found the Holy Grail of hormone replacement therapy (HRT), a large prospective clinical trial in healthy postmenopausal women, in the initial report from the Women's Health Initiative. But, rather than providing definitive data showing an overall benefit of long-term HRT use, the study found that combined continuous conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA) increase the relative risk of breast cancer, coronary heart disease, pulmonary embolus, and stroke and decrease the relative risk of hip fracture and colorectal cancer.[1] The significance of these findings is accentuated by the recent decision to end this arm of the larger WHI after a mean follow-up of 5.2 years, rather than the planned 8.5 years, when the observed increased risk for breast cancer crossed the predetermined threshold for terminating the study. Both the study findings and the early termination are likely to have a major impact on current, former, and prospective users of HRT and the healthcare providers they look to for guidance and care. We have all been eagerly anticipating this information, and now we must interpret it carefully and reorient our thinking to reflect the arrival of high-quality scientific data on a prevention strategy that has been based on less robust studies.

Although disquieting to many, including women who have used or are using HRT and the providers who have encouraged them to do so, the WHI data and the recent similar findings from HERS II[2] come as no great surprise in view of the initial HERS reports of an increased risk of venous thromboembolic events and no overall protective benefit against coronary heart disease (CHD) with the use of CEE/MPA in women with preexisting CHD.[3] Moreover, multiple analyses of observational studies of breast cancer risk have predicted a time-related increase with HRT use. Now we have solid evidence of that risk with the use of CEE/MPA and an estimate of the magnitude and onset. Similarly, the findings of fewer hip fractures, less colon cancer, and more gall bladder disease[4] in subjects on CEE/MPA are all consistent with observational studies and add better data to our understanding of the impact of HRT.

Perhaps most frustrating for proponents of HRT and vindicating for detractors is the evidence that CEE/MPA not only does not decrease CHD risk but increases it, albeit modestly in terms of actual risk. This finding is a marked contrast from most observational studies on which the concept of HRT for prevention of CHD was based. It fails as a long-term prevention strategy, at least by 5.2 years in WHI and 6.8 years in HERS II, and the early increase in risk overshadows any potential subsequent benefit. It also underscores our limited and assuredly incomplete understanding of the full biological effect of sex steroids throughout the human life cycle.

These data fundamentally change the frame of reference for all prescribers of HRT, particularly the generation of providers steeped in the conviction that the long-term benefits outweighed the risks and any good prospective trial would surely validate that assumption. No longer can we cling to the belief that long-term HRT is the best strategy for most women, but must maintain a healthy skepticism that our replacement strategies are an improvement on normal ovarian aging except to alleviate significant symptoms. We must now recognize that these tantalizingly limited data call into question the long-term benefit of all combined continuous estrogen/progestin replacement regimens. Moreover, they raise the possibility that replacement therapy with estrogen alone, or with raloxifene or any of the selective estrogen receptor modulators (SERMs) in development, may have no long-term protective benefit against CHD or may actually increase CHD risk. This accentuates the significance of the continuing CEE-only arm of the WHI and the ongoing Raloxifene Use for The Heart (RUTH) trial in determining the role of replacement estrogen as a desirable option for healthy aging or merely as a short-term strategy for intolerable symptoms. It is highly likely that the results of the WHI will be generalized to all HRT and ERT regimens, despite being limited to CEE/MPA only, and will drive the collective thinking about HRT for the immediate future.

Many criticisms can be, have been, and will be leveled at these studies. Perhaps chief among them is the limitation of both studies to a single combination of oral hormones used primarily and dominantly in North America at the time they were both initiated. The specific hormones and route of administration may have significantly affected the results, and a number of alternative HRT combinations not studied are now in clinical use today. Also, the duration of WHI was arguably not "long-term" at 5.2 years, especially in view of the long lag time for the development of breast cancer. But, the long-term benefit would have to be quite dramatic to outweigh the small but significant early risk of CEE/MPA, and the trends in both studies showed no indication of such a dramatic shift.

The immediate dilemma is to apply the significant findings from these studies to specific patients, many of whom are on different regimens and/or have specific clinical needs . One could argue that many of our patients have solved that problem for us by deciding to discontinue HRT without consulting us or by deciding not to fill the prescription in the first place[5] -- a source of great frustration to many concerned with poor "compliance" to HRT regimens. We will need to have clear indications both for initiating and continuing HRT, we will need to carefully inform our patients of the actual risks and not just the relative risks, and we will need to outline alternatives in a balanced and unbiased manner. With the WHI and HERS II data, alternatives may include ERT alone (if the estimated risk of endometrial cancer is outlined and an appropriate monitoring strategy adopted), statins for CHD risk, and bisphosphonates for bone preservation.

If we truly believe that good data direct good practice, then there is no question that these long-anticipated studies direct us to modify our practices to reflect them. Many practitioners have been doing so since the original HERS study was reported, and many patients have been doing so when the symptoms from the HRT they were taking outweighed the immediate benefit they were noting. The primary indications for HRT have not changed: the relief of vasomotor symptoms and vulvovaginal atrophy. Beyond these relatively short-term perimenopausal and early postmenopausal concerns, CEE/MPA appears to have more risks than benefits for most women. This redirection in thinking for many of us, and many of our patients, will require us to assume even greater roles as providers of health information as well as providers of traditional healthcare.


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