The headline news that the estrogen-progestin arm of the Women's Health Initiative (WHI) was being halted - because the increased risks of invasive breast cancer, coronary heart disease, stroke, and pulmonary embolism outweighed decreases in fractures and colorectal cancer - has had physicians' phones ringing with women asking for advice about this "sudden change." But much of the news was not indeed "new" - and the risks identified are very small. Thus, for many physicians, the WHI announcement will not have a significant impact on their clinical practice.
The theory of estrogen replacement sounded logical: continue a hormone women lost after menopause, not merely to ease initial menopausal symptoms, but also to help prevent bone loss and because it might account for women's later-than-male development of cardiovascular disease. The epidemiological studies backed up both concept.
The first serious "wake-up" call came with the results of the Heart and Estrogen/progestin Replacement Study (HERS) in 1998. It suggested that hormone replacement therapy (HRT) might have no benefit in preventing cardiovascular events in post-menopausal women with underlying heart disease - and might even be detrimental. Thus, it was theorized that women in the general population who used HRT were different from non-users - had better health habits and risk profiles, which accounted for their lower CVD rates in epidemiologic studies.
Further, evidence that long-term use of HRT might increase breast cancer risk slightly have also been around for years. More recently, an international panel of experts concluded that there was little evidence to support many of HRT's presumed benefits.
Now, the WHI - an NIH-sponsored study of 27,347 post-menopausal women (most of whom did not have underlying heart disease) has yielded the following estimated hazard ratios:
These numbers got blown up in the media into relative risks that sounded terrible. It may be easier for your patients to understand their meaning in terms of absolute excess risk (as further explained in the JAMA article): for every 10,000 "person-years," there were 7 more cardiac events in those who took HRT compared to those who did not - 8 more strokes, 8 more pulmonary emboli, and 8 more invasive breast cancers. That sounds a lot less threatening, although certainly worthy of the clinician's attention.
Such an interpretation also can change the way patients interpret the benefits of HRT, which yielded the following hazard ratios:
Thus, there were 5 fewer hip fractures per 10,000 person-years. Patient response depends on how you "frame" the risk.
It is still unclear whether estrogen alone has the same risks as estrogen and progestin; thus, the estrogen-alone arm of the WHI is continuing - although that arm enrolled only hysterectomized women because of the long-known (significantly higher) risk of endometrial cancer due to unopposed estrogen.
While ethics required the WHI to discontinue the trial, in view of the wide range of risk factors likely present in their nearly 30,000 enrollees, that does not mean that HRT necessarily presents serious risks to any individual patient.
The WHI news has not changed our practice at the Osteoporosis Center at the Hospital for Special Surgery. While we do not prescribe estrogen as the initial therapy for women with osteoporosis, we might consider prescribing estrogen or a SERM (raloxifine) in those who are not responding adequately to bisphosphonate therapy. (A SERM may be chosen if the patient has a family history of breast cancer.)
If a woman is already on estrogen at the time of low bone mass diagnosis, it guides our therapy because it is well documented that estrogen will reduce fractures by about 25 to 30%. Nothing further need be added if the woman chooses to stay on estrogen and continues to have osteopenia and a stable BMD.
However, if a patient decides to discontinue estrogen, we can expect bone loss over the ensuing one to five years similar to the bone loss seen after menopause - from 2 to 5% per year loss of BMD. Patients who discontinue estrogen should be monitored closely for bone loss with DEXA and, perhaps, urine n-telopeptide. Patients who are osteopenic or osteoporotic probably should be prescribed another anti-resorptive agent, since bone loss will be expected when they discontinue HRT.
Physicians understand science keeps shifting and that clinical trials are all imperfect, but patients usually have a harder time, especially when they have long been taking a pill that suddenly seems to get bad press.
Many women have taken estrogen for years without side effects. In certain patients - particularly those who are slim, healthy, and without a personal or family history of breast cancer - estrogen may be beneficial and pose little risk. However, when patients have their yearly follow-up, it is appropriate for the physician to reassess the benefits and risks in that individual patient - and how these may have changed over time - and make a recommendation about initiating or continuing use of HRT. Here's the balance sheet to keep in mind.
The benefits of estrogen for alleviating hot flashes and night sweats are proven. Short-term HRT probably poses little if any risk to those slim, healthy women. Even in patients whose cholesterol is controlled by a statin and whose blood pressure is well-controlled, if no previous thrombosis has occurred, it appears safe to take HRT for a limited period of time (up to five years) to control post-menopausal symptoms.
At intervals over the years, tapering can be undertaken. For example, with Premarin dosing, the patient could be moved from .9 mg to .625 to .3 to zero over a period of months. If hot flashes recur, the patient can be maintained on the lowest possible dose to control symptoms.
If HRT is discontinued and vaginal dryness occurs, topical estrogen can alleviate atrophic vaginitis.
The bone benefits of estrogen are outlined above; bisphosphonates are more potent - and SERMS less potent - than HRT in preserving BMD.
The cardiovascular and breast cancer risks are outlined above. There is also an increased risk of formation of gallstones and cholecystitis with use of any estrogen - whether oral contraception or HRT.
At the Osteoporosis Center at Hospital for Special Surgery, our first choice for treating women who are osteopenic or osteoporotic is a bisphosphonate (alendronate or risedronate). They are far more efficacious than estrogen at reducing the risk of fracture and have a better safety profile. If the patient has a prior history of gastric ulcer or related gastric problems or cannot tolerate a bisphosphonate, we recommend a SERM (raloxifine), although SERMs also carry a risk of thromboembolism.
For prevention of cardiovascular disease in patients with high cholesterol levels, a statin or other cholesterol-lowering medication should be prescribed. Statins not only lower cholesterol but have been shown to reduce the risk of heart attacks. It is still controversial whether they may also reduce bone resorption and have anti-inflammatory benefits.
In conclusion, while a large, randomized, controlled trial such as the Women's Health Initiative is certainly welcome, evidence from smaller trials has long suggested most of its findings. This trial only confirms the appropriate use of HRT.
 Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002 Jul17;288(3).
 Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998 Aug 19;280(7):605-13.