Getting the Women's Health Initiative (WHI) & Estrogen... Straight.

WHI Details. Still solid today.

This is what I wrote in Safe Hormones, Smart Women.

This book was, in essence, a scientific deep-dive and response to the inappropriate fear and interpretation of the WHI 1. I also wanted to do a scientific data sleuth as I had had ER+ breast cancer and wanted to take hormone replacement therapies.

Since publishing the Mercola estrogen rebuttal, many have written to me sharing how confused they are. So thought this would be helpful.

There are no debates.

If you follow the science.

The science, and even the first WHI 1, shows that estrogen is breast protective.

Even oral Premarin. (Though we prefer natural sex steroids).

But because Premarin is an oral estrogen, meaning it is swallowed, it was linked to not an increase in breast cancer, but an increase in heart issues. Swallowing estrogen takes it through the digestive tract, making some possibly unhealthy heart molecules in the liver.

But there is no longer any debate.

Estrogen is breast-protective.

Here is my chapter from Safe Hormones, Smart Women on getting the WHI 1 straight.

THE WOMEN’S HEALTH INITIATIVE—
THE CRISIS

The Women’s Health Initiative (WHI) was started to clear the air about the use of HRT. It was prematurely stopped in 2002 and suddenly HRT was regarded as dangerous. Over the next few years, many criticisms started to emerge but didn’t make headlines like the scary ones did. Many experts now believe these findings can’

For years women have been given hormone therapy to “treat and prevent” everything from heart attacks to bone disease and to keep them looking more youthful. Throughout multiple decades, many “observation” studies (meaning groups of women were observed and followed to figure out if hormones did in fact help them) suggested that hormone therapy earnestly kept menopausal women healthier and more trophy-like.

But there were flies in this ointment that wouldn’t go away:

·      The question of reality. Do women who use hormones really get better, or is it just a “healthy user bias”? This means that women who choose to go to the trouble of using hormones take better care of themselves in general, and it isn’t just the hormones that are making them healthier and younger.

·      Real scientific proof. In contemporary scientific thinking, the gold standard of proving that something works is when the substance (in this case, hormone therapy) passes what is called a double-blind placebo controlled randomized trial. This type of study shows whether a substance authentically works beyond chance. If so, then docs can hang their clinical treatment hats on it. This is the foundation of evidence-based medicine, proving that a remedy works beyond a shadow of a scientific doubt. Historically, many (not all) hormone studies were observational instead of randomized and blinded.

These buzzing “flies” created background “noise.” Since millions of women around the world were on hormones over the decades, scientists and doctors wanted to know for sure: Do hormones really do what we are telling women they do? Or not?

The pressure was on. These questions needed to be answered once and for all by performing gold standard, randomized trials. And they needed to be run on thousands of women, which meant using multiple centers around the country (which gives the results more weight).

We had wanted this type of well-respected study on hormones for decades. It was needed. The world, women, and doctors were waiting for hormone therapy to be scientifically vindicated.

Research scientists and medical doctors alike thought that such a study would uphold hormone therapy and be the final proof in the pudding that hormones were good for what ailed most menopausal women.

So began the big enchilada of hormone studies: the government’s well-intentioned, randomized controlled trial, The Women’s Health Initiative, which was started in 1991 and was to run for fifteen years. It was set up by the National Institutes of Health (NIH), along with every other prestigious government institution this side of Alaska.

The WHI was huge. The entire hormone industry was hanging on the results of this one study. It was going to be the definitive word on hormones. Everyone was excited.

The WHI was conducted at forty clinical centers nationwide. Wyeth, the giant pharmaceutical company, supplied the government with its combination drug Prempro™ (horse estrogen plus synthetic progestins) to be used in the trials. Everyone thought the WHI would end up confirming that horse estrogen and synthetic progestins were good medicines.

What exactly was the WHI looking at?

It wanted to find out what to do about aging. Since more Americans and global citizens are aging, we need to have effective policies to help. So the WHI was set up to look at the most common causes of death and disability in menopausal women: heart disease, cancer, and bone loss. It had three randomized, double-blinded trials and one observational study to test how hormones, low-fat diets, and calcium and vitamin D affect the quality of life of pausal women.

Everyone was sure hormones would be proven to be the universal anti-aging remedy.

A total of 161,808 women (fifty to seventy-nine years old) were enrolled between 1993 and 1998 (each of the separate trials had smaller groups of women).

First Hormone Trial—Women on combined hormone therapy

(the “plus” means the numbers were slightly higher)

·      Group 1 — 8,000-plus women on Prempro™ (horse estrogen and synthetic progestin)

·      Group 2 — 8,000-plus women on placebo (an inert non- medication given to the control group)

·      Second hormone trial—Women on horse estrogen only

·      Group 1 — 5,000-plus women (without uteruses, given estrogen-only Premarin™)

·      Group 2 — 5,000-plus women w/o uteri on placebo

So what happened?

The study began. A number of years passed, and suddenly In July 2002, the first hormone trial ended prematurely. With lots of bad press.

It triggered a major upheaval in hormonal plate tectonics. The authors of the study told the biomedical world that the women on this combination hormone protocol (horse estrogen plus synthetic progestins) started having more heart disease, breast cancer, stroke, and lung blood clots.¹²⁵

The WHI authors were saying that HRT gave women the very diseases that it had been thought to prevent and treat.

It was announced that the risks were greater than the benefits. Understandably, docs got upset; women got terrified. The benevolent perception of hormone therapy was changed forever—or so it seemed at that time.

This reversal initiated a hormone crisis of epic proportions. Women abandoned their prescriptions.

Doctors refused to write them.

The American Heart Association recommended that long- term hormone therapy not be used for prevention of heart disease (remember, it had even been given to women after heart attacks to prevent recurrences).

But then …

Two years later, the second hormone trial (ladies on horse estrogen only, without synthetic progestins) ended prematurely (2004) due to more bad news: Estrogen-only therapy seemed to increase the risk of stroke while not helping hearts.

One doctor, Jerilynn C. Prior, the scientific director for the Centre for Menstrual Cycle and Ovulation Research, pronounced: “The Age of Estrogen ‘Replacement’ is now over.”

Hormone therapy was largely abandoned. Women became estrogen-a-phobic. But was it a case of shooting ourselves in our ovaries? Yes. Something had gotten lost in translation.

This estrogen-only study had also demonstrated encouraging results about estrogen and breast cancer that seemed to pass a lot of doctors and women right on by.

Added to that, over the next few years, numerous well-respected scientists and physicians scrutinized the results of the WHI trials, finding that the conclusions were, in their words, wrong.

The risks found in both studies were much smaller than had first been announced.

They discovered that the design of the study didn’t show what it said it showed.

There were lots of issues, and the results weren’t as bad as had first been reported.

Let’s dig more deeply into this confusion and see if there isn’t a safe and healthy way to use hormones after all.

When I heard the announcement of the results of the Women’s Health Initiative, I thought how ridiculous, we are now going to throw the baby out with the bathwater. Since I started practice in 1983, I have discussed with my patients the pros and cons of bioidentical and synthetic hormones—estrogen, progesterone, adrenal, thyroid, and a few others. Patients are educated, smart people, and the best person to decide a medical or natural treatment program is the person who will be receiving that treatment. This is always true as long as the risks and benefits are known, can be explained to the patient, and the patient is competent to make that decision.

—Christine Green, MD

The Green Hormone Balancing & Lyme Clinic

The good news from the second hormone study

The good news was a surprise. Women in the second group on horse estrogen only had less breast cancer. After 7.1 years on horse estrogen by itself (without added synthetic progestins), the women in the second hormone trial were found to have 18% less breast cancer compared to women not on estrogen.¹²⁶ (Don’t forget that horse estrogen contains male and progestin-like substances, so even though it is an estrogen, it is somewhat of a combination hormone product. Keep that in mind. I think that when you look at the balance of studies, taking estrogen with bioidentical progesterone is the smartest approach.)

When this data from the second WHI hormone study was analyzed again (they went back and made sure they looked at women who really had taken the estrogen), this is what they found:

·      Breast cancer (localized to breasts) was reduced by 31%.

·      Ductal breast cancer was reduced by 29%. Wow!^{127 128}

·      There was an apparent protective effect of the horse estrogen on breast cancer incidence in all categories for women at lower risk (women who didn’t have first-degree relatives with breast cancer and who didn’t have benign breast lumps and bumps).

·      Women who had been on synthetic progestins in the past (before this estrogen-only study) were at greater risk.

• Those on estrogen only before this study weren’t.

·      After 7.4 years on estrogen only, younger women (fifty to fifty-nine years of age) monitored by sophisticated imaging studies actually had slower growth of calcified plaque in their arteries, meaning they had a heart-protective effect from the estrogen.¹²⁹

Then a flurry of similar studies started to emerge.

One large study followed 374,465 postmenopausal women (fifty to seventy-nine years old), the hormones they took, and their risk of getting breast cancer. While women on both hormones (estrogen plus synthetic progestins) had a greater risk of getting breast cancer, women on estrogen without progestins for more than five years had an 8% decreased risk of getting breast cancer compared to women not taking hormones.¹³⁰ The women on estrogen had less breast cancer than women not taking hormones!

Even though there have been some studies that show an increase in breast cancer after short-term use of estrogen (given with synthetic progestins), a bunch of promising studies were starting to build up showing the opposite: that estrogen doesn’t hurt breasts and may in fact slightly protect them (if given without synthetic progestins).^{131 132 133}

This is significant.

The second arm of the WHI and other studies were starting to suggest that women on hormone therapy may have some protection against breast cancer.

But who heard this good news?

Mention hormones today and women mentally grab their breasts in fear.

When I lectured in the summer of 2009 with Dr. Eldred Taylor (Board-Certified OB/GYN, author, and hormone replacement expert) to a group of gynecologists, internists, and family doctors, it was striking that few had heard about these promising results from the second WHI study. Many of my medical doctor friends still have not heard about this information.

And on top of the positive trends that weren’t making it into public consciousness, now criticisms of the whole WHI—how it was run and what conclusions it had drawn—began to surface throughout the scientific scene.

In an article titled “Women’s Health Initiative is fundamentally flawed,”¹³⁴ the authors (from Loyola University Stritch School of Medicine) said that the findings of the WHI were wrong. These researchers summarized criticisms from numerous colleagues and experts across the United States who challenged and proved that the WHI was greatly flawed and its conclusions largely inaccurate.

Fred Naftolin, PhD, a scientist from Yale who is also on the executive committee of the International Menopause Society, was worried that doctors were denying women a chance to take estrogen and as a result were actually withholding solid preventative health care, especially for their patients’ hearts.¹³⁵

Why do we hear so many scary headlines about hormones?

In a nutshell:

Good news doesn’t sell; bad news does.

One study looked at how the media presented the hormone issue to the public. It was found that the media more often gives studies headline status if they show increased risks from taking hormones as compared to studies that show hormones are safe. Then those scary headlines understandably resonate and replay in our minds. Many women reasonably fearful about taking hormone replacement.¹³⁶

What about headlines stating breast cancer rates have gone down since women went off hormone therapy?

The scary results from the WHI came out in 2002. The rate of breast cancer decline started in 1998, 4 years before women went off hormones.

The media, and even scientific studies, attributed the recent breast cancer decline to women going off hormones en masse when the first part of the Women’s Health Initiative came out in 2002. This proves, they said, that hormone replacement therapy was causing the increase in cases of breast cancer.

But if you read the literature, breast cancer rates had started to go down several years before the WHI results came out, and before hormone therapy use sharply fell off.

Dr. Christopher I. Li, from the Division of Public Health Science at the Fred Hutchinson Cancer Research Center, looked at data from thirteen cancer registries from 1995 to 2004 to get a handle on what was causing changes in breast cancer incidence. They found that cancer rates started to go down around 1998, well before 2002 when the WHI brouhaha hit the media. These authors say, as many others now suggest (though not all), that the decline is probably due to more and improved breast cancer screening.¹³⁷ They did say that further declines might occur related to the decline in HRT use, but remember that the hormones most often prescribed and used in the United States—and then largely “thrown out the window”—were mainly horse estrogen combined with progestins, a mix that has not proven good for breasts.

Other studies suggest other analytical reads on breast cancer rate trends. The Epidemiology and Surveillance Research team at the American Cancer Society recognized a sharp dip in rates in predominately estrogen-positive tumors from 2002 to 2003 when so many women went off HRT. But it acknowledged that going off hormones didn’t explain the start of the decline in 1999. It also noted that one type of breast cancer—in situ breast cancer, whose rates had been rising since 1981—were stable from 2002 to 2003. ¹³⁸

Criticisms of the WHI

·      The design was flawed

·      It only used one protocol of hormones

·      The age of the participants was skewed older

·      The majority of the women were heavier (a huge breast cancer risk factor by itself)

·      There were too many dropouts among the participants

·      The recommendations could not be validly generalized to all women

·      Many of the conclusions were not accurate.

Surveys all over the world were sent out to doctors by local gynecologic societies. Doctors answered questions about what they now thought of hormone therapies and the WHI recommendations. The international results from various countries consistently demonstrated that doctors who had been prescribing hormones to women for years and had seen positive results in the clinical trenches did not believe the alarming results of the WHI. But because of fear (litigation, confusion, questions), most U.S. doctors understandably had stopped writing scripts. However, many doctors in Europe kept writing scripts for lower dosages and transdermal applications of hormones.

Over the next few years, more concern spun out. Criticisms mounted regarding the results, the design of the study, and the recommendations, which were now said to be inappropriately generalized to all women of all ages for all hormones. In fact, the outcomes were based solely on only one hormonal protocol (horse estrogen plus synthetic progestin) being tested on older, heavier women, with a one-formula-fits-all higher dose and oral application.

In 2006, in OB GYN NEWS, Dr. Leon Speroff, Professor of Endocrinology and Gynecology, wrote that the risks posed by the results of the Women’s Health Initiative Study are incredibly small, and perhaps even non-existent. This is now what many experts think.

The biggest criticism was that the average age of patients in both WHI hormone trials was sixty-three and most of the women had gone through menopause more than ten years earlier. In clinical practice, most women start hormone therapy around the time of the perimenopause, not a decade or more later. Thus, the results of this study clearly could not be extrapolated to the general public, as Dr. Charles Hammond wrote in his paper on the WHI and its implications for clinical practice.¹³⁹

Dr. Edward L. Klaiber, a consultant endocrinologist at the University of Massachusetts Medical Center, was the lead author of an article published in 2005 in Fertility and Sterility that criticized the WHI results. Klaiber’s major criticism was that because these women were older, they were already at greater risk of cardiovascular problems and strokes. He pointed to previous findings from the large-scale Nurses’ Health Study, in which women were placed on hormone therapy at a younger age (in their forties and fifties) and did not take the combination continuously used in the WHI. In these women, hormones protected their hearts.

A summary of how scientific journals around the world see the WHI now (when I published this important book)

^·             The women in the WHI were older, less healthy, and more overweight and had not been producing hormones for ten years. This situation doesn’t replicate how hormones have been used for decades—giving them to younger women when menopause first starts.^{140 141 142 143 144 145 146 147 148}

^·             Younger women in the WHI got lots of health benefits. Those who initiated hormone therapy within ten years of the start of their menopause had a reduction of heart disease by 12 to 52%, and death from all causes was reduced by 30% compared to women not on hormones.¹⁴⁹

·      The reason the second hormone study was stopped was because an increased risk of strokes was seen. But it turns out they were mainly seen in older women, not the younger women fifty to fifty-nine years old.¹⁵⁰

·      The WHI hormone trial designs had serious flaws that blew the risks of hormone therapy way out of proportion to what actually happened.^{151 152}

·      Excessive participant dropout weakened results. The percentage of women who stopped actively participating in the WHI study was 42% in the HRT and 38% in the placebo group after the mean study duration of 5.2 years. The estrogen-only arm seemed to protect against breast cancer.^{153 154}

^·             The WHI didn’t look at lower  dosages  or  transdermal delivery.¹⁵⁵

^·             Conclusions from the first WHI hormone trial did not agree with results from many studies looking at thousands of women up to that date of 2002.¹⁵⁶

·      The results shouldn’t be generalized to all postmenopausal women.¹⁵⁷

·      Comments also include the fact that the trial did not test the natural estrogens (estradiol or estriol) more commonly used in Europe and Asia. And women were given hormones every day of the month (continuous delivery), which may not be as safe as cycling hormones (taking some time off each month to give the body a rest).

The Women’s Health Initiative trials—the “purest” scientifically based studies run by our government and many prestigious institutions— were well-intentioned and sincerely tried to reach evidence-based information on hormones. But they turned out to be somewhat of a statistical fiasco that exposed the weakness of the concept that one medicine fits all and one study tells all.

And the results of the WHI fly in the face of doctors being doctors.

Dr. Leon Speroff reminds us that “a clinician’s knowledge is greater than what is read in the medical literature; it includes an entire and on- going education, and not to be neglected, experience—the knowledge gained from each and every patient encounter … Perhaps the greatest lesson of the Women’s Health Initiative is the awareness that a single study is only one view of the truth.”¹⁵⁸

That very sentiment is seen in one 2007 survey sent out to American OB/GYN doctors by the Department of Research at the American College of Obstetricians and Gynecologists (ACOG) in Washington, DC. Questionnaires went out to 2,500 American doctors, all fellows of ACOG. These responses revealed that many gynecology doctors expressed skepticism about the negative results of the first arm of the Women’s Health Initiative. The second arm of this study (the one many people don’t know about) showed that estrogen appears to protect hearts, breasts, and longevity in younger menopausal women. In the surveys, these same gynecologists were less skeptical of these different results and thought they rang more true.¹⁵⁹

Many doctors who have worked with hormones for years in their practices didn’t really want to stop using hormone replacement and didn’t earnestly believe hormones were as dangerous as suggested. For example, in Israel in 2004, 95% of questioned docs at an annual gynecology convention said that they still believed hormone therapy was the best, safest treatment for menopause. But 65% told their patients to go off it, and 40 % of their patients demanded to be taken off it.¹⁶⁰

Most authorities are now saying that the best hormone replacement needs to be personalized for each woman.

Hormones demand customization because each woman needs a different amount and diverse hormones based on her own needs. Then each woman needs to be monitored and her hormones tweaked according to her response. This kind of individual attention doesn’t lend itself to the FDA template of testing a whole group of women with the same exact experimental substance versus a control group—an enormous problem in trying to do a standardized study on one singular hormone replacement regime and its effects on large numbers of individual and diverse women.

Dr. Steven R. Goldstein was a key-note speaker at the 62^nd annual conference of the American College of Obstetrics and Gynecologists. During an interview I asked Dr. Goldstein about his thoughts on the WHI. Dr. Goldstein said, "The estrogen-only arm of the WHI showed almost none of the harms that were seen with the estrogen-and-progestin arm. However, that arm got very little attention, and many younger women who could benefit from estrogen replacement therapy are not getting it!”

The “older” interpretation of the WHI led many doctors to recommend HRT for the shortest time and for symptom relief only, thinking that the risks far outweighed the benefits.

Now we know this is wrong. It’s the other way around.

HRT benefits far outweigh the risks.

We all worry about our brains.

Findings from the Cache County Study published in the Journal of the American Medical Association in 2002 showed that the incidence of Alzheimer’s disease (AD) was reduced by 30-50% in HRT users.

Women on HRT for more than 10 years had a 5-fold (500%) lower incidence of AD.

You need to be on it long-term to protect your brain as less than 10 years didn’t give as much protection. Initiating HRT at the onset of menopause, as you shall see, is the safest way to go.

Don’t waste time, go get tested.

Dr. B.