Menopausal Hormone Therapy and the Women’s Health Initiative

If you are reading this and are not a physician, please keep in mind: Scientific proof is not nearly as black and white as people think, and In order to make treatment decisions for individual people sometimes we have to consider evidence that is not nearly as absolute as we would like. This is not meant to be medical advice, and you should consult your own physician for any medical issues or diagnoses you may have. 

Many of you already know what the women’s health initiative was and the Disastrous results its release had on the evolution of Menopausal Hormone Therapy and women’s health. For those who don’t, bear with me for a minute while we talk a bit about the history of women’s hormone replacement.

Before the mid-20th century, suffering through menopause was an inevitable part of being female in the human world, with all the consequences to women. Hot flashes, loss of sleep, mood disturbances, memory loss, and about 90% loss of interest in sex among many other symptoms, as our eggs ran out and ovaries declined in mid-life.

Then Premarin (Conjugated Equine Estrogens or CEE) was manufactured from pregnant mare urine and introduced in the 1940s, and Hallelujah, all those symptoms could be stopped! As medicine advanced, it was discovered that using Menopausal Hormone Therapy not only eliminated those symptoms but it was eventually observed that the replacement of Estrogens would significantly reduce  many longer-term conditions  that were known to be associated with declining Estrogen: 

• Bone loss
• Collagen loss from the skin, joints, and other tissues
• Increased rates of depression
• Dementia
• Diabetes
• Coronary and heart attack risk
• Stroke risk
• Gallstones 
• And even increased cancer risk. 

Things went along fine for a while, and Premarin was the #5 most prescribed medication in the USA.

Then a popular book called “Feminine Forever” was released in 1966. In it, the author Robert Wilson likened menopause to “Chemical Castration” and recognized the right of women to “youth, beauty, and a full sex life”. Unfortunately, he pitched MHT as something women should do in service to men’s desires rather than for themselves. It rightfully incited a firestorm of feminist backlash, and it was later revealed he had been funded by the manufacturers of Premarin.

Then in the 70s, it was observed that endometrial cancer risk rose 4-8 x in patients treated with oral Estrogens alone, but that this risk could be mitigated by adding a chemical Progestin to the estrogens to reduce the proliferation of the uterine lining. (bio-identical micronized progesterone did not exist yet) So Provera (medroxyprogesterone acetate MPA) was born.

As things went on, more and more evidence accumulated that Estrogens could reduce the risk for Cardiovascular disease, which in premenopausal women was less than men's risk but quickly “caught up” after menopause. The huge Framingham study reported 50% reduction in hip fracture deaths, 40-50% CVD, 50% decrease in colon cancer, 35% reduction in Alzheimer’s, and no increase in BrCa even when MHT was used for 15 years. And lifespans on average 3 years longer!

Another very large study - the Nurses’ Health Study -  released in 1991 seemed to confirm these benefits and reported 50% reduction in heart risk among Nurses who used hormone therapy. But it was plagued with “Healthy user bias” so researchers were concerned whether the benefit was real or not. Healthy user bias means they could not be sure that the benefit was due to the treatment or the fact that the women who chose the treatment were more health conscious and therefore healthier in the first place.  Scientists also continued to worry about the safety of MHT.

This prompted the creation of the Women’s health initiative by the NIH.

A huge study, the researchers set out to “prove the cardiovascular benefits of MHT” starting in 1991. This was a prospective, randomized trial,  40 centers, and many authors! over 27,000 women

There were two parts to the study:

• The first part was women who had undergone hysterectomy - they were given Premarin alone or placebo.
• The second group was women who had not undergone hysterectomy - they were given Premarin Plus Provera (Prem Pro or “CEE plus MPA”) or placebo.
  
  

They chose PremPro purportedly because it was the prevailing MHT treatment at the time. (but looking at the drug company grants to some of the principal investigators makes one wonder).

According to Jo Ann Manson MD, who is now the lead author of the ongoing analysis of the data, they chose women who were in menopause but had no symptoms, because they rightly believed that women given placebo would drop out of the study when they realized that the treatment was not stopping their hot flashes and other symptoms. Women who had recently undergone menopause were therefore under-represented in the study samples. How did they find so many? (Remember menopause symptoms are present in at least 73% of women and can persist 10 years or more past onset) They had to choose women who were at least 10 years past menopause. Also, since their aim was to prove or disprove Heart Disease protection, they chose women of an age where that finding was more likely to show up sooner. Older women - so they “could get significant results faster” according to one of the study’s designers. The average age of the women was 63! Also, the assertions that they were ”healthy” were not true!  35% were significantly overweight, and another 36% obese. Obesity alone confers an elevated risk of Breast cancer. Over 50% were smokers! So they could not have picked worse candidates on whom to initiate HRT if they had tried!

Then in July 2002… Jacques Rossouw and 2 other lead investigators stopped the study (they neglected to say just the CEE plus MPA arm) and went to the press! Even before the printed scientific results were published. He told the press that the risks of HRT outweighed the benefits: “NIH has stopped early the WHI, a major clinical trial of the risks and benefits of Combined estrogen and Progestogen in “healthy” menopausal women due to an increased risk of invasive breast cancer” 

They went on to say:

Compared with a placebo, (the estrogen and progestin) HRT was shown to cause an “increased risk of heart attack - 29%, increased risk of stroke - 41%, increased risk of blood clots - 50%, increased risk of breast cancer, reduced risk of colorectal cancer, fewer fractures, no protection against mild cognitive impairment, and increased risk of dementia”. The increased risk of getting breast cancer was given as 26%.

They said they were stopping the study because the results “approached clinical significance” and went to the news before the preliminary results were even published. They made no mention they were quietly continuing the CEE alone arm of the study. The news headlines then read: Estrogen causes Breast cancer!!!! And no amount of explaining or re-analyzing has been able to reverse that false belief from the American Psyche.

And over the years that followed they continued to update the results and insist that the results justified their alarming reporting methods. But they were not correct, because, by the time the study ended in 2006, the apparent increased risk had vanished in all arms of the study.  And they failed all along to emphasize the fact that the estrogen-alone arm did not increase breast cancer risk: almost all the adverse seeming outcomes were happening in the CEE plus MPA arm and not from Estrogens.

Robert Langer, one of the investigators on the study, finally went public in 2017, saying that originally, the bulk of the investigating researchers had been “actively excluded from correcting critical misinterpretations” in the findings before the original study went to press. Why did they do it?! It reeks of conspiracy. The answer lies in the social psychologic phenomenon called Confirmation bias. Confirmation bias is the tendency of humans to look for data that confirms a strong belief that they already have (such as hormones are bad) and ignore all evidence to the contrary.

One principal Investigator - Jacques Rossouw-  had a known agenda… He was a cardiologist who was convinced for some reason that replacing hormones was risky and ill-advised. in 1996 when the study had barely begun he published an editorial that indicated he thought someone should “put the brakes on the HRT bandwagon”. Well, he did just that! He was also quoted after the press conference as saying his intent was to “shake up the medical Establishment” and that they were “intentionally going for high impact” in releasing the findings the way they did. Another PI said, because the study was as large and expensive as it was, and the question was as important as it was, that “the statistical police have to leave the room”. All these instances reveal that the unbiased attitude needed for good science was absent in the 2 men who were principally in charge. They needed to justify the mind-boggling expense of NIH money on some significant findings!

Rossouw also started out by saying that the findings had “broad applicability,” emphasizing that the trial found no difference in risk by age. It would be years before researchers appreciated just how wrong that was. Later analysis showed improved heart risk in women under 60. Risk doesn’t reach significance unless hormones were first started by women 70 and over.

They tended to use data mining to “prove” their points. This is a way that studies with large data sets can be manipulated and reported to “prove” almost any finding.

Just about any result a researcher wants can be “proven” by mining down into the data deep enough, and by excluding logic. Here’s an example:

 A huge analysis of many research studies reported in 1997 found that there was no increased breast cancer risk in women who had used HRT in the past, no matter how long they used it! But they found a 0.6% increase in a subset of women who were currently on HRT and had been taking it over 5 years. (details of how many women this was was not reported) but it should be obvious that the researchers were looking for any subset they could choose that justified their belief!! that HRT caused an increase in cancer. The smaller the subset, the more likely it is that random chance caused the results.

There was one other Swedish study that was cited as showing increased risk in a subset, 8 excess cancers in the E&P group, but once again the subset of E alone showed a decrease in risk. Once again, they had narrowed things down to where the size of the sample was small enough that random chance was likely to have given the result they reported.

It’s understandable that people are worried about Breast cancer. It is common enough that 1 in 8 women will contract it if they live to age 85. But statistically, it is nowhere near as deadly as heart disease. Up to 90% of women who are treated for breast cancer will be cured without a recurrence. Heart disease is present just as often but kills 10x as many women. Colon cancer also still kills over a third of those who contract it.

It’s also true that there are problems with MHT, given as it was when this study began. The use of PremPro had become institutionalized. There was ONE dose. It was not measurable or detectable in women’s blood as true Estradiol and Progesterone are. No one knew what the optimal dose was to minimize side effects, or what specific agents were best with the least side effects. Or which women needed which hormones. Few physicians were trying the newer and potentially better formulations and administration methods as they came available. Pre-treatment labs were not done to see who needed it. People were continued on it despite not knowing for sure if there were long-term risks. and there are! A few! with Provera in particular. But the risks are not what they said.

There is an increased risk with Provera and blood clots, about double the general population. This risk is the same increase seen with some oral contraceptives and pregnancy. Women accept these risks as a matter of routine, to not become pregnant, or to become pregnant. Some physicians are OK with women taking this risk with HRT. I am not, because FDA-approved Progesterone, identical to what’s natural in our bodies, does not carry this risk.

So let’s look at that. The risk in general of contracting Breast cancer between ages 50 and 60 is 2.33%, so a 26% increase in that risk is now 2.94%. (contrast that to smoking which increases cancer risk by 2600%)  But what they neglected to emphasize was 1. This apparent result was seen only in the CEE + MPA group. 2. It was caused by the lower-than-expected standard positive cancer cases seen in the control group for that subset (turns out a significant number of participants in the study had been on HRT before the study started and carried (speculatively) lower risk than they were thought to have going in!. and 3. That result (Increased cancer and cancer deaths) disappeared over time as the groups were followed longer and longer.  And all the while, quietly, the Estrogen alone group was showing Lower risks of Breast cancer than the controls.

They selected women least likely to benefit and most likely to suffer complications: Fatter patients with no symptoms, who were older & longer post-menopause than usually start HRT. They gave them a one-size-fits-all treatment with horse estrogens and pseudo-hormones never experienced by healthy human physiology.  Even so, they did not show a significantly-increased breast cancer risk. 

This fact did not make national headlines. The actual final results? Premarin alone actually gave a statistically significant reduction in Breast cancer of about 25%.

Did good come out of the WHI? In a word, YES.

1. It taught us that the timing of starting hormone therapy matters. The closer to the onset of menopause you are when you start MHT, the more the benefits and the lower the risk. Women who are 10-20 years out from menopause have some increased risk with less benefits, and starting MHT at 20 years and beyond past menopause seems to increase risk and provide minimal benefits compared with early replacement. 
2. It taught us that synthetic Progestins, particularly MPA, have problems, the most concrete one being pulmonary emboli and elevated clot risk, but there is also a statistical trend towards higher Breast cancer risk.

“Believers” since then are trying to improve the treatment paradigm.

How?  

• By understanding normal physiology & hormone balance
• By using the laboratory to identify and follow patients’ hormone levels
• By giving “real” hormones in benign doses via safe routes 
• By listening to our patients! 

That's it for now! I'm Dr. Dana Gibbs of Consultants in Metabolism, encouraging you to take charge of your hormonal health. For more tips and updates, sign up for my newsletter at https://www.danagibbsmd.com/email-list-form. If you're in North Texas and struggling with thyroid or chronic fatigue issues, visit https://www.danagibbsmd.com/cim-medical for a new patient evaluation.