Crystallograph of estradiol, one of the key forms of estrogen. In the wake of last summer’s cessation of the Prempro arm of the Women’s Health Initiative, physicians and patients alike are struggling with questions on how best to manage estrogen deficiency following menopause. Image courtesy of Michael W. Davidson, Florida State University.

If you are like most physicians, you’ve been fielding a lot of anxious questions about hormone replacement therapy lately.

The media whirlwind following cessation of the Prempro arm of the 16,000-plus patient Women’s Health Initiative (WHI) sparked nothing short of a crisis of faith for many women, leaving doctors scrambling to put the findings in perspective.

For clinicians trying to follow the ongoing HRT saga, and for the 14 million women who have been taking HRT, the post-WHI score card seems to read: HRT, five strikes. But, be advised that five strikes don’t mean HRT is out.

In early July, the National Heart Lung and Blood Institute grabbed lots of headlines—but surprised no one—when it stopped the estrogen-progestin (Prempro) arm of WHI, perhaps the most anticipated study of the last decade. Rather than protecting women from cardiovascular disease, HRT was associated with a 41% increase in strokes, a doubling of venous thromboembolism, a 29% rise in heart attacks, and a 22% increase in all CVD. Top that off with a 26% increase in breast cancer, and you’ve got the makings of a world-class panic.

On the upside, though, Prempro was associated with a 37% reduction in colorectal cancer, a 33% decrease in hip fractures and a 24% decrease in all fractures. Overall, HRT had no net effect on mortality. So why all the angst?

Partly because the WHI findings revealed what many people—physicians and patients alike—often prefer to ignore: that key therapies within mainstream medicine are not nearly as evidence-based as many would like to believe.

The fact is, there was never any data from a “gold-standard” randomized controlled trial that HRT was truly cardioprotective. The assertion that HRT could prevent CVD was based on plausible biological mechanisms and made sense based on retrospective population-based studies of pre- and post-menopausal CVD incidence. Hundreds of thousands of women were prescribed HRT based on a cardioprotection rationale, though there was no first-tier science to back it.

According to Tori Hudson, ND, a women’s health expert who teaches at both Bastyr University and the National College of Naturopathic Medicine, the charge leveled against many natural therapies—that they are based more on conjecture than data—could have equally applied to the HRT-cardioprotection claim. Only, nobody ever applied it.

“If you ever feel bad about the natural therapies you are prescribing not being supported by RCTs, just remember there was complete consensus that women needed HRT even if they were not at risk for CVD, and all without an RCT. In 1998, they did the first RCT, sponsored by Wyeth Ayerst, and they were blown away to find no overall effect on primary or secondary events,” Dr. Hudson said at the annual meeting of the American Association of Naturopathic Physicians.

The study Dr. Hudson cited was the landmark Heart and Estrogen/Progesterone Replacement Study (HERS) II trial. But HERS II was simply the largest pre-WHI study to dash the cardioprotection claim. It was not the first. A number of smaller prior trials, including the Estrogen Replacement and Atherosclerosis (ERA), Estrogen in Women with Atherosclerosis (EWA), Papworth HRT Atherosclerosis Study Enquiry (PHASE), Postmenopausal Hormone Replacement Against Atherosclerosis (PHOREA), and Estrogen and Prevention of Atherosclerosis Trial (EPAT), all called the claim into question.

The issue did not hit national headlines until the American Heart Association took a giant step back from HRT. In July 2001, AHA, which previously promoted HRT as cardioprotective, told doctors to stop prescribing it as a means of preventing heart disease, and warned that giving hormones to women with existing CVD could increase heart attack and stroke risk. Last summer’s WHI Prempro shutdown was simply the final nail in the cardioprotection coffin.

Lori Mosca, MD, PhD, who authored the 2001 AHA science advisory statement, said the WHI findings were widely anticipated given all the secondary prevention data suggesting HRT had the potential to do more harm than good.

But Wulf Utian, MD, executive director of the North American Menopause Society is still withholding judgement. Though he acknowledged the importance of the new data, he stressed that HRT remains the best treatment for menopause symptoms such as hot flashes, sleep disturbances and mood swings. The caveats provoked by WHI should not be interpreted as a categorical dismissal of HRT.

He and other exponents of HRT emphasize that the aborted WHI trial pertained only to one form of HRT. Prempro, though the most popular form, is not and never was the be-all, end-all of HRT itself.

Only two weeks after WHI delivered what some thought was a knockout punch to HRT, researchers meeting in Stockholm at the 8th International Conference on Alzheimer’s Disease and Related Disorders (IADRD) suggested that estrogen is neuroprotective. While it may not protect the heart, it appears good for the brain.

The findings, based on preliminary analysis of data from the Swedish Twin Registry, indicate that this protective effect is not related to length of estrogen therapy. Nancy L. Pederson, PhD, professor of genetics and epidemiology, University of Southern California, Los Angles, California, and a co-investigator in the Twins study, said the data confirm earlier observations that “estrogen is clearly protective of the central nervous system.”

WHI is not completely dumping HRT either. It is continuing the estrogen-only arm that follows healthy women taking estrogen following surgical menopause.

But women seem to be voting with their wallets, and they’re clearly voting against Prempro. Sales have plummeted since the WHI announcement. Some women are also taking legal action. One class-action suit has already been filed against Wyeth, and more are sure to follow given the number of law firms with websites seeking to marshal women who’ve used the product.

Wyeth Pharmaceuticals announced on September 6 that it would relabel both Prempro and Premarin, the conjugated equine estrogen product still under investigation in the estrogen-only arm of WHI. The new labels, stating estrogen should not be taken to prevent heart disease and should be taken for as short a time as possible, were drafted with the Food and Drug Administration.

The new labels also advise doctors and patients to consider other alternatives for prevention of osteoporosis. More meetings on HRT are scheduled throughout the fall. The labels might again be revised.

Michael Zeligs, MD, who has researched the use of compounds derived from cruciferous vegetables that regulate estrogen metabolism, stressed that, “all HRT is not created equal.” WHI findings cannot be extended to predict the effects of other forms of HRT, particularly bioidentical estrogen and progesterone.

Given the wide variety of bioequivalent hormone products, not to mention phytoestrogens from soy, Red Clover, Black Cohosh, and lignans from flax seed, there are many potential approaches to alleviating menopausal symptoms and preventing CVD, osteoporosis, and other health challenges for women in mid-life.