BY MARYANN B. BRINLEY

Looking back on the summer storm of controversy surrounding the safety of hormone replacement therapy (HRT) and 15 million fearful women, Norman L. Lasser, MD, PhD, principal investigator of the Women’s Health Initiative (WHI) study site at UMDNJ-New Jersey Medical School, has to shake his head just a little. Lasser helped deliver a "bombshell that created many more ripples than expected" with the shocking news that HRT using the most commonly used combination of estrogen and progestin in America, Prempro, was not as beneficial as conventional wisdom and observational studies had assumed. In fact, after five years on the drug, the risks were deemed so definitive by the Data and Safety Monitoring Board (DSMB) of WHI, that when this group met in May to look at the most recent statistics on the health of their 27,000 volunteers, the members decided to end the Prempro part of the nationwide clinical trial which was supposed to continue until 2005.

"Everywhere I went, women said, ‘Hey, you’re the guy who is taking away my pills,’" Lasser recalls. Newspapers and media outlets picked up the WHI turn of events and ran wild with it from the press conference and official announcement on July 9 until well into August and September. Some reporters were angry. Many patients were confused. A lot of gynecologists didn’t know quite what to say to their non-stop phone-callers. Exaggerations and partial truths made headlines: how could millions of women have been duped into taking a daily, dangerous pill that causes heart disease, breast cancer, and strokes? To answer this question and address other misconceptions raised in the debate over HRT, Healthstate spoke to Lasser as well as Gloria Bachman, MD, associate director of women’s health for UMDNJ-Robert Wood Johnson Medical School (RWJMS) and a co-investigator on WHI, and Adam Perlman, MD, MPH, recently appointed executive director of the Institute for Complementary and Alternative Medicine (ICAM) at UMDNJ.

"To all those women who were suddenly frightened, I say the news isn’t really that bad," Lasser explains. He dismisses talk of successful lawsuits being mustered against Wyeth Pharmaceuticals, the makers of Prempro. "The increased risks of heart attack and stroke are so small for the individual woman that there is no good way you can say the drug is responsible." A close examination of the actual coronary heart disease (CHD) numbers published in the Journal of the American Medical Association (JAMA) on July 17 by the Writing Group for the WHI investigators, shows that of 8,506 women taking Prempro, 164 developed CHD, but in the placebo group of 8,102 participants, that number was 122. Moreover, Bachman emphasizes, "We actually saw lower rates than what was expected in the general population. All these women did very well in terms of cardiovascular disease."

What summer news reports often missed was the fact that treating any disease or acute symptom with a medication is different from taking that same drug for preventive reasons. "When you give somebody a preventive drug, whatever bad it does has to be less than the good reason for taking it. The best analogy is a vaccine," Lasser explains. Out of a large group, some are going to have ill effects from a vaccine, but if the goal is to prevent a life-threatening disease like smallpox, for instance, then the benefits outweigh the risks. The threshold for stopping this clinical trial for adverse effects was set very low because its aim was prevention. Meanwhile, the actions of the 12-member DSMB, which met every six months to examine data and protect WHI participants, were controlled by that low bar. When risks crossed the boundary, they had to stop the trial. Yet, in real life, there are risks and benefits to everything we do. Taking diabetes medication poses risks. Even that aspirin a day to reduce the danger of a heart attack has pitfalls. Bachman likens this issue of risks versus benefits to driving a car. "We could be in a fatal accident but if the car is the best way of getting from A to B, then we don’t outlaw cars. We try to minimize the risks by wearing seat belts or following speed limits."

Never approved by the Food and Drug Administration (FDA) for any preventive purpose, HRT had grown into a "magic bullet" and a $2.75 billion industry for good reasons. "Was it pseudo-science which led everyone down this HRT path?" asks Perlman. "No, we practice medicine based on the best evidence available at the time coupled with our own experience, the patient and our personal expertise. Now, our best evidence available has changed."

First manufactured from pregnant mare’s urine, the drug Premarin was approved by the FDA for the treatment of hot flashes and other menopausal symptoms in 1942. Even now as some women worry about long-term consequences and look for alternatives, the truth is that nothing works as well, or has been tested as much, as exogenous estrogen (Premarin) or estrogen in combination with progestin (Prempro), for this purpose. "There are always concerns about quality when you are dealing with herbal alternatives," Perlman says. Substituting a natural, or plant based, estrogen for a synthetic product raises complications. "What I would emphasize is that bio-identical estrogens (not from pregnant mare’s urine) are available, may control symptoms of menopause and be beneficial but these things are even less researched than the FDA-approved drugs. I never like to assume that just because it’s natural, it is safe." (See box on "Unraveling Alternative Answers.")

The WHI study did not examine hot flashes, night sweats, insomnia and all the other reasons women take hormones during menopause, including skin changes or the aging effect that loss of estrogen may have on cognitive function. Bachman points out, "It only answered a specific question, so this is not the only study on which use or disuse of HRT should be based. This is an individual decision and each woman is going to weigh her own risks versus benefits." For instance, the effect on the central nervous system of severe vaso-motor symptoms—hot flashes which can last far longer than the oft-cited, general rule of three to four years and possibly up to eight, ten or even thirteen—is unknown, according to Bachman. "Are women doing damage to receptors by not taking hormones to plateau out these raging ups and downs?" Such issues were never figured into any benefit/risk ratio formula by the WHI.

Because Prempro and its placebo cousin, donated by Wyeth, were the only drugs tested, the WHI results apply only to one particular formulation of .625 mg/d of conjugated equine estrogens plus 2.5 mg/d of medroxyprogesterone acetate. Rival companies were knocking on doctors’ doors to push their products, and sales pitches for alternatives to HRT reached an unprecedented hype in August, but even less is known about the safety and efficacy of these preparations. "There are no other clinical trials looking at any other HRT clinical product," Lasser says. "Anything said is not based on hard proof."

Meanwhile, questions regarding the appropriate dose of HRT remain. One size certainly doesn’t fit all women, as many articles pointed out, but more often than not, the standard had been supersized unnecessarily. Pharmaceutical companies routinely study drugs in high concentrations because manufacturers need to see side effects and the higher the dose, the more likely this will happen. Thus, the common prescription eventually marketed for consumers is also high, according to a recent report in the journal Pharmacoepidemiology and Drug Safety.

In the case of HRT, many women were being given more estrogen than their bodies originally produced. In effect, excess hormones may have been causing side effects, not just replacing those being lost as a result of menopausal shifts. Variable female cycles and lack of definitive testing capabilities precluded reliable data about the proper dose back in 1942 and for most women, that perfect dose is still a mystery. Measuring hormone levels, using serum or saliva testing, is possible but not a probable route, according to Bachman. In the meantime, a chorus of recommendations to reduce HRT dosages was heard last summer. "We may be able to use effectively a .3 but we don’t need to tailor it to the drop," Bachman explains. Starting with the lowest possible dose, patients will now be watched to see when symptoms disappear and moved up to a higher concentration, if problems persist. Rather than erring on the side of "too much," standard practice for use of HRT to control symptoms of menopause, will likely move to a "too little" approach now.

"I think there are several take home messages from this WHI study and one of them is that you can never generalize," says Bachman. Each woman is different. Some are symptomatic with health effects in menopause that can’t be downplayed. "I may have three times the amount of estrogen as my next-door neighbor for my entire life," Bachman says. Body size is not necessarily a predictor and all women lose estrogen at different rates. Ovaries, one of the organs which produce estrogen, can begin to stop functioning five to six years before the end of menstruation, or the start of menopause. "We need to look at measuring hormones throughout the life cycle and may be starting too late to think of preventive interventions at age 50, 60 or 70. What the WHI study results told us is that we didn’t see benefits in the cardiovascular area for women who started at the average age of 63 and most of these women had not been on hormones before."

In the heat of the debate, when reporters were ganging up verbally on researchers, editorials criticized a book, Feminine Forever, allegedly underwritten by Wyeth, for putting a positive spin on the estrogen story early on. The truth is that this hormone’s reputation as a wonder drug grew "little by little," Lasser explains. "There were no malicious motives on the part of the drug company. Good things were coming out in observational studies," he recalls. "If you draw a figure of a woman and map out all the parts of her body possibly helped by estrogen, you almost cover the entire body, from the brain down to the bone." All these effects are very well established and some are recent. News about protection against osteoporosis, colorectal cancer, and Alzheimer’s disease, as well as the hormone’s ability to improve libido and provide myriad benefits, was available for years.

"Hormones were assumed to be safe because they are a natural product," Lasser explains. "We now know that they can do bad things." In the 1980s, incidences of uterine and endometrial cancer in women taking estrogen alone, rose. Sales and prescriptions of Premarin fell. Then, researchers learned that by adding a progestin such as medroxyprogesterone, or Provera, to Premarin and creating Prempro, this risk could be diminished. Anyone taking estrogen after a hysterectomy had no need to worry, of course, because the threat of cancer of the uterus had been removed. In fact, one WHI group is continuing with the Premarin part of the trial.

Over the years, the theory gained momentum that estrogen could reduce the risk of heart disease, the number one killer of women. Numerous large and small observational studies appeared to prove this "off-label" or unofficial use. Wyeth funded one project, the Heart and Estrogen/Progestin Replacement Study, known as HERS, to pin down the heart benefit in women who already had heart disease. HERS was the first clinical trial to show no heart benefit and results were published in 1998 before any WHI findings were known. Later, what became apparent to the unblinded DSMB is that all those prior observational studies and common assumptions could not compare to the value of a large, long overdue, clinical trial. Behind the scenes within the WHI hierarchy, everyone was truly shocked when the numbers didn’t go in the right direction. At the outset of their work in 1993, WHI organizers hadn’t even thought to include CHD as a possible risk on the consent forms because all effects on the heart were over on the benefits side of the equation.

Though women would like to be angry and doctors may have been puzzled with researchers, the heart benefits in particular were so significant and reported so often in a 10 to 15 year period, that no one could ignore those recommendations. "It looked like HRT offered a 40 to 50 percent reduction in heart disease," Lasser says. During child-bearing years, women have only one-fifth the risk of death from heart attacks as men. After menopause, that statistic goes up and physicians always assumed that hormones offered the protection. As it turns out, just "losing a lot of estrogen alone doesn’t make this risk go up," according to Lasser. Incidence of heart disease rises slowly after menopause and should have offered clues to the nature of female biology. A woman’s risk of cardiovascular disease inches up after menopause but doesn’t reach a man’s level until she is in her mid-eighties. If hormones alone were the only culprit, heart disease numbers would jump suddenly in menopause.

Frightening headlines about the possibility of breast cancer and blood clots obscured another truth: these worries had always been on the warning labels. "Those WHI findings were not surprising," says Bachman. These potential side effects, especially that elevated risk of breast cancer, were already in every Physician’s Desk Reference. "The shame in having to stop the study is that we may never know what was promoting the cancer. It usually takes seven years for breast cancer to develop." Only 5.2 years had passed. American College of Obstetricians and Gynecologists (ACOG) recommendations for clinicians treating female patients also appear to allay breast cancer fears. In the WHI slides presented last summer, researchers pointed out, "The majority of studies have not found increased risk of breast cancer with ERT/HRT use." And, "tumors diagnosed in women using ERT/ HRT generally are smaller, have a lower grade and are less aggressive."

Lasser adds, "Our own statisticians also muddied the waters because they didn’t report the way the breast cancer data was studied to make the decision to stop." Their approach weighted the breast cancer numbers according to when they occurred and followed standard protocols but the data reported did not reflect this, so the increased risk looked significant. Each year, breast cancer, which can never be taken lightly, remained part of the WHI statistical puzzle, more value was added to the number, which didn’t increase much by itself. Simply put, "the longer the events occurred in the data, the more weight they were given," Lasser says. This risk "actually did not turn out to be any higher than what we told participants it would be when they signed up for the study," according to Lasser.

One heated probe which came up repeatedly was: how could such a standard medical practice have gone on for so long without a large, clinical trial proving its efficacy? Money was certainly a factor. Clinical trials, like WHI with a price tag of $750 million, are prohibitively expensive. Meanwhile, other types of scientific investigations can be unreliable. Researchers usually start with an observation and then go looking for associations or evidence to prove their assumptions. Sometimes only specific subjects (women already taking HRT, for example) or animals are used. These kinds of studies, while helpful, can’t really prove cause and effect. Only a randomized, controlled clinical trial can do that. Participants are unaware of who has been assigned the real drug, and who is taking the placebo, and investigators are also "blind" to this data. Hence, the work is called "double-blind."

However, money wasn’t the only reason it took decades for the National Institutes of Health (NIH) to undertake a definitive, randomized, double-blind trial with 161,861 women. Large clinical trials had only been conducted with men for at least three other reasons. Women with their variable hormonal cycles were believed to be difficult to study; more men than women were dying of heart attacks in the prime of their working lives; and, to be honest, because men "were running things," Lasser admits.

In 1990, the newly appointed and first-ever female Director of NIH, Bernadine Healy, MD, had a mission: to put women’s health on the research map. In spite of the drawbacks, "the idea of such a large clinical trial had been kicked around before," Lasser recalls, "but nobody really wanted to spend the money." Healy, who only held onto her NIH position for two years, successfully pushed to have the funding approved without the usual scientific review by Congress, as a separate line item. Rolling three studies (diet, calcium/vitamin D supplements and HRT) into one, Healy has been criticized, but Lasser and other WHI investigators credit her political savvy. With no Healy at the NIH helm now, Bachman underscores "the critical importance of clinical trials as one of the messages we can all learn from this WHI data," and suggests that women write to their senators, congressmen, and representatives demanding "these trials for our health. This is the only way medicine can ever move to the next step or make real breakthroughs."

Drug companies simply can’t afford such financial gambles. Though preventive, or "off-label," markets may appear lucrative and worth investigating, look at what happened to Wyeth in the wake of the WHI trial’s halt. The drug company’s stock lost $15 billion in just one day in July after the announcement and by September 1, sales of Prempro had dropped 30 percent.

No inside story about HRT would be complete without a peek at the dilemma presented to the WHI team. In Chicago on June 27, Lasser and other investigators were stunned with the simple announcement by the acting WHI director Jacques E. Rossouw, MBChB, MD, from the National Heart, Lung and Blood Institute (NHLBI): "We’ve decided to stop the study." The chair of Lasser’s steering committee had been called earlier and a small writing group had already written a paper with the findings which was ready for the NIH website and JAMA. The editor at JAMA had even pulled an issue from publication to accommodate WHI and rush the results into print. "The news was dropped on us just before lunch," Lasser says. Each member was handed a copy of the galleys of the completed article and the unblinded data to read before the group took a break. Slowly, "It dawned on us," he recalls, "this might be the most important finding of the entire study."

Should ordinary physicians with lots of worried female patients have been left in the dark when their phones started ringing? Lasser explains, "While it could have been presented to ACOG first, we didn’t want our WHI participants to read about this in the press before they were officially alerted." Investigators needed them to stay in the study and they are still coming. "We just aren’t giving them a pill anymore," he says. (When given the news of what they had been taking, some women who had credited Prempro for high quality of life while part of WHI, were surprised to learn they were actually on the placebo.) Because of the decision to keep the results as secret as possible until the press conference, physicians were left out of the loop and, as a result, they couldn’t answer questions confidently. Scores of HRT prescription users didn’t even try to reach their doctors and simply quit pills cold-turkey, which was never a good idea, according to Lasser. One of his own cardiovascular patients who had been on HRT for 13 years for menopausal symptoms and has a medical history that includes colon cancer in her family, was told by her gynecologist to stop taking the HRT and just drink some soy milk. Lasser suggested that she go back on HRT when her menopausal symptoms, including insomnia, returned and because of the bone protection offered. However, he plans to revisit that recommendation as new data analyses are done.

Every HRT decision—to stop, start, stay on and for how long, including the dose and form (pill, patch, cream)—must be very personally tailored. The WHI results showed only that hormones should not be taken primarily to prevent heart disease. The jury is still out on many aspects of the evolving science of hormonal therapy. Bachman says, "HRT products are still an important part of our health care, a piece of the puzzle for many women and just one part of the health equation."