As a layperson, I wonder what the study would have shown had progesterone been used instead of progestin. But why would such a study even be attempted? There is no money to be made by marketing a compound that can't be patented...
You left out the elephant in the Women's Health Initiative study--all subjects received conjugated equine estrogen + progestin (IIRC the study was sponsored by Wyeth (clearly in hopes that their HRT product, Prempro, would get a boost from the study results, rather than being so dramatically shot down!)). To then generalize (as you have throughout your post) from equine conjugate to all HRT (and then writing as if all HRT is the same formula) is at best imprecise and at worst, sloppy. So I think your strong conclusion, despite all the impressive statistical analysis, misses a crucial point.
Even back in 2000, I thought equine conjugate was a bad idea because potential for immune system interactions. There are other HRT formulas: human recombinant estrogen, formulas using estriol, with or without progestin. Unfortunately, many of the alternative HRTs are compounded, with no large RCTs to guide clinical judgment.
Also, cardio-protection is not the only, nor from the user's standpoint, the most important, reason to choose HRT.
The 19-year re-analysis of the WHI found it had many many issues. For one, they forgot to control for women historically who had taken ER (estrogen therapy) in the placebo arm. Dr. Leon Speroff began early on showing the many issues with the WHI. Then Naftolin, the Yale statistician. Then my book, Safe Hormones, and then the 19-year re-analysis by 12 prestigious institutions, the very original authors of the first July 2002 published WHI findings, retracted their original study!!!! Their new reanlysis, 19 years later, hind site is better than foresight, found clearly that estrogen replacement (with Premarin in this case - ER., was statistically linked to a 23% reduced risk of getting breast cancer and a 44% reduced risk of fatality if you got this disease if you had taken estrogen. The new NIH 7 million medicare study is a retrospective observational study showing decreased all cause premature mortality if on ER, and a significant reduction of all five cancers (colorectal, lung, breast, ovarian and uterine) and only oral had increased risk of ischemic stroke and dementia while the other modes, especially vaginal, were CV and CA protective. None of the large European studies showed issues with HRT and in fact so much benefit that HRT is given for free in many countries to help protect their medical system as the hormones protect their citizens so much, such as Finland, Iceland, Wales, Scotland, italy, on and on and even Britain got in on this a year ago with a sliding fee schedule but free for those making much less money. Why? Socialized medicine and tracking their registries, like CV, CA and death registries, show such consistent benefit. It all depends on which science you are looking at. I have been on HRT for about 26 years a few years after I had breast cancer, almost 30 years ago now. And... going strong.
The following link is the textbook level of evidence based medicine. There is no way to put this politely. Almost nobody here is even at the textbook level of expertise in philosophy of medicine.
I was doing physics research in '84. We were never taught Evidence Based Medicine back then, but we limped along somehow without it. My research had implications for diagnosis in medicine.
Pulse oximeters use a similar technology, but in a different region of the infrared and at a simpler level.
My thesis didn't include any fancy statistics, but a couple of years after I published it, some journal editors asked me if I wanted the journal to retract an article that was very similar to my thesis work. That really surprised me.
My thesis defense committee profs asked my one question each. My answer for each was, "I don't know, but I'll look into it and get back to you." It turns out that that was the correct answer.
We all have blind spots. We all make mistakes. Game theory applies to research and always assume that data is cherry-picked until proven otherwise and that money drives research until proven otherwise. There are many ways to game research.
I appreciate your point but I'm afraid the example you chose to cite is a poor one. You were more correct on your first assertion. We've got 18 yr follow-up studies on HRT/MHT demonstrating that 20 yr study was poorly designed and newer studies found that women taking any type of HRT have a lower risk of heart disease, osteoporosis, diabetes, dementia, death, and also colon cancer, and other cancers as well. Women taking any type of HRT are less likely to die from breast cancer. It's assertions like these, based on old science, that contribute to millions of women not getting adequate treatment for menopause and unnecessary suffering. https://www.nhmenopausesociety.org/research/hormone-therapy-why-we-should-no-longer-be-afraid-of-the-breast-cancer-risk-says-new-literature-review/
In spite of the flaws in the WHI study, as identified in previous comments, the conclusion of the article is correct - RCTs are the only way to prove medical efficacy over a large population. Could John have found a more valid RCT to support his thesis?
RCTs can be so flawed that their results are misleading and dangerous, as in the reported WHI study.
Studies which focus on mortality end points can leave out the real-world trade-offs between risk of death vs quality of life. We face such trade-offs every time we decide to travel or even to drive to the grocery store and, unfortunately, statistics will never give us a clear way to strike a balance.
Case in point: my wife has been on HRT for over 20 years, starting around menopause. ObGyn's often don't approve, as a result of the WHI study, and we have to pay for her HRT drugs because Kaiser won't. But the symptoms she has experienced any time she has gone off of HRT have been more than adequate to convince her to resume HRT. Fortunately, she has a trusted non-Kaiser health professional who is supportive of HRT. The balance is between the certainty of symptoms that make her miserable vs the possible (now largely discredited) increased risk of life-threatening disease.
It seems to me that any study like the WHI should at least document the difference in quality-of-life symptoms between the placebo and intervention arms of the study. Did WHI do this?
There's no such thing as "bad cholesterol". In fact, there's no such thing as "high cholesterol". The idea that LDL causes heart disease is nonsense and I can't believe in this day and age that doctors still believe it.
Here's one of literally thousands of articles I could post showing there's no association between heart disease and "bad cholesterol".
This is an excellent review outlining a common foible in clinical intuition leading to observational research which is not yet science. HRT started in the 1950s when a cardiologist in Massachusetts noted that HRT not only relieved postmenopausal symptoms but seemed to lower the incidents of CVD and AMI among his patients. The rest is history. Your story omits the part where Wyeth (then Wyeth-Ayerst, then Pfizer) the manufacturers of Premarin (a proprietary mixture of estrogens actually extracted from horse urine) spent huge amounts on advertising to make certain this product dominated the market and was demanded by many women. It gained huge cultural acceptance. The large controlled randomized study you cite was necessary to break this advertising juggernaut.
You also omitted to note that while P/E HRT significantly increased the risk of breast cancer in women, Premarin and other E only HRT increased the risk of uterine cancer 500% more.
Thank you for pointing this out. It’s amazing how many people still don’t know how Premarin is sourced (look it up). Premarin named for: Pregnant Mare Urine. Of course horse urine estrogen isn’t healthy for human women! I don’t need any study to tell me that.
For all the women more concerned about HRT than maybe the overall point of this writing, I'm not seeing what type of HRT was administered. Premarin and estradiol are definitely different drugs. Within a few months of a hysterectomy, premarin caused deep indentations in nails and my hair continued to fall out in large amounts, for months after the surgery. A friend educated me about the horse urine used in the drug, the side affects and about plant based estrogen. The estradiol had no side affects (for 25 years). This is anecdotal and probably doesn't apply to a majority of women, but if you are in need of HRT for whatever reason, the information may be helpful.
I fully agree. Transdermal bioidentical estrogens plus progesterone and testosteone have been a godsend for me for the last 20 years (study n=1). Since the formula is compounded, it can be tweaked as necessary for best results.
For a comprehensive article and very lengthy annotated "links and references" section, see "Bioidentical Hormone Estrogen Prevents Heart Disease," March 15 2013, by Jeffrey Dach, MD.
Abstract [excerpts:] "Conventional hormone replacement therapy results in increased thrombotic events, and an increased risk of breast cancer and dementia as evidenced in large prospective clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women's Health Initiative. A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors....
"Subjects receiving compounded transdermal bioidentical hormone therapy showed significant favorable changes in: Greene Climacteric Scale scores, Hamilton Anxiety Scale, Hamilton Depression Scale, Visual Analog Pain Scale, fasting glucose, fasting triglycerides, MMP-9, C-reactive Protein, fibrinogen, Factor VII, Factor VIII, Insulin-Like Growth Factor 1, and health outcomes of co-morbidities and a number of prescribed medications.
"Antithrombin III levels were significantly decreased at 36 months. All other measures did not exhibit significant effects. Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women. Cardiovascular biomarkers, inflammatory factors, immune signaling factors, and health outcomes were favorably impacted, despite very high life stress, and home and work strain in study subjects. The therapy did not adversely alter the net prothrombotic potential, and there were no associated adverse events."
Except that the same WHI group published research 15 years later showing that HRT has no impact on all-cause mortality at all. The 2002 study was flawed and caused much misery to women benefitting from but subsequently denied HRT. Scare-mongering like "HRT led to a nearly 50k women being harmed" needs to stop. doi:10.1001/jama.2017.11217
See my comment above. The '02 study was done on a single drug formulation, oral equine conjugate, which even at the time (when I was making my own HRT decisions with my MD) I thought was a bad formula (cross-species immune reactions, oral route through GI & liver, etc.). To generalize from one RCT to all HRT (as if all HRT is the same as Prempro) is not careful analysis.
So true. While the WHI is a good example of how observational studies are flawed (HRT for everyone), it is also a good example of how RCTs can be flawed. As a result of the secondary analyses mentioned above and newer studies, the prevailing opinion among reproductive endocrinologists at least (if not internal medicine docs) is that in many women the benefits outweigh the risks if HRT is started early ie within 10 years of menopause. It is very effective for vasomotor symptoms and vaginal dryness (FDA approved indications) and "may" even decrease the risk of CVD (although not FDA-approved for that indication). HRT was also shown to decrease the risk of colon cancer in WHI, a finding that received relatively little attention in my opinion. I tend to prefer to prescribe FDA-approved bioidentical formulations (ie 17b-estradiol and micronized progesterone) although the data is out on whether or not they are in fact better or safer than synthetic hormones.
In many ways, the cholesterol hypothesis of heart disease provided the blue print for big pharma during the covid crisis. The heart attack ‘epidemic’ sweeping America during the 50’s was heavily promoted in the MSM but was almost certainly due to better technology for testing and changing disease classifications. Academics who disagreed with the cholesterol hypothesis were scapegoated, ridiculed and denied research funding. An expensive ‘antidote’ to heart disease (ie the various statins that have been manufactured over the years) was developed and given to a willing public.
Meanwhile, the evidence that over consumption of saturated and/or animal fats cause heart disease remain, 70 years later, ambiguous at best. The evidence that statins provide benefit to all but a sub-group of highly at-risk patients also remains stubbornly ambiguous. The safety profile of these drugs is certainly up for debate and not helped by clinical trial organisations (CTSU in Oxford, I’m looking at you!!) withholding accumulated safety data from the public
Wonder where we’ve seen all this happen over the last two years.......?
Another great example that STILL is directing patient care erroneously is the observation that patients who get iodinated contrast may have increases in serum creatinine. Worse- it was conflated to iodinated contrast can cause not just creatinine rises, but renal failure. When a matched control study was done, it was found that the hospitalized patients who did NOT get iodinated contrast had the same amount of rise in serum creatinine that hospitalized patients who got iodinated contrast had. Iodinated contrast had no role in the creatinine rise. Yet, still, patients are refused the benefits of a CT scan with contrast because of this fallacy.
It is indeed complicated. Observational Studies can be biased. A single large RCT might be flawed, too. I think, here is some critique on that RCT: https://m.youtube.com/watch?v=DTCmprPCDqc&t=4210s
A couple items. First, all “studies” begin with a single observation. It’s the genesis, the seed, for an hypothesis then a testable theory. So observational studies are powerful in that they guide innovation. A serious problem with studies looking for statistical power is the systematic introduction of error that can dilute or eliminate real effects that are actually real as observed in the case study. This happens often when the suspected treatment agent is only effective when interacting with a second unidentified factor, or there is an unidentified factor responsible for the observation. Jumping to a parametric study will only find no effect and the discovery is lost. Second, in the HRT study the assumption that E reducing LDLs as the mechanism reducing cardiovascular events is errant leading to the finding of no effect in the parametric study. Many studies have shown that cholesterol is not the relevant factor in CVD, the relevant factor is vascular inflammation. In fact, the relevant variable in the study mentioned is actually vitamin D status and its effects on reducing inflammation hence CVD. So, while E is a minor agonist of vitD, the heavy lifting with respect to CVD was vitD. So here we have that second unidentified, unappreciated, ignored? variable that is responsible for the observed effect. Don’t get me started on why vitD, a free, safe, readily available agent is systematically villified/ignored by the medical community. I think it has something to do with $$$.
John I wish you expand your thoughts with regard to two issues: (1) you are emphasizing relative risks rather than absolute risk increases; these absolute risk increases seem small per woman, and (2) women take HRT for a reason and place some value on the benefits received. Shouldn't those values be formally traded off against the (small) absolute risk increases? As an aside I'd like to see us de-emphasize the multiplication of risk by some population size, and concentrate on what the risk is per-person.
the 2002 JAMA study cited actually concludes there was no difference in all-cause mortality, suggesting absolute risks around one very big indicator--death--were not different between the groups studied.
Ok, but still referencing old study/findings. IMS summarizes new analyses:
Key points
-In women under age 60 and recently postmenopausal with no evidence of cardiovascular disease, the initiation of estrogen-alone therapy reduces coronary heart disease (CHD) and all-cause mortality [A]
-Data on daily continuous combined estrogen–progestin are less robust but other combined therapy regimens appear to be protective as shown in Danish and Finnish studies [A]
-Recent meta-analyses and WHI 13-year follow-up data all show a consistent reduction in all-cause mortality for MHT users [A]
-It is not recommended to initiate MHT beyond age 60 years solely for primary prevention of CHD [A]
Good points. The absolute risk increase IS small for women on HRT. Some women benefit a lot from HRT but now have to endure browbeating at every checkup, lectures about heart disease, stroke etc. HRT can improve sleep when menopausal symptoms cause wakefulness; one of my sisters, a very fit retired Navy vet, says she's willing to take her chances on the hormones because without them life is hell due to insomnia from hot flashes. I know women who've been cut off cold turkey by overzealous obgyns, a pretty destructive move. Individual health and low absolute individual risk have to be considered and weighed, and the patient educated.
The risk is not as small for perimenopausal women as for post-menopausal women, iirc. So grouping all women together lends itself to Simpson's Paradox.
Thank you. We are training doctors to practice population-based medicine and to worship EBM & algorithms, and we are not attracting critical thinkers to medicine. As a result, we will see more people turning to naturopaths and chiropractors for care. We deserve the loss of trust we are experiencing. Unfortunately, medical schools seem to be embracing the corporate and communist takeover (what do we call that, when the communists are taking over the corporations?).
This is the perfect description for what's happening.
Fifteen years ago my health (at 42) was headed in the wrong direction. I was overweight, my eyesight was bad, I had hand tremors and had recently diagnosed with asthma. My doctor put me on an inhaler to help with the asthma and he told me I'd need it for the rest of my life and the dosage would increase as my asthma progressed. I did it his way for a month and gained 10 lbs due to the steroids in the medication. I then did my own research, did a simple diet change (low carb) and my asthma disappeared almost overnight. Additionally I lost 40 lbs, my hand tremors disappeared and my eyesight improved to the point where I no longer need glasses. How many people out there can say that their eyesight got better as they got older?
I'm 57 today and after 15 years of much reading I now know that doctors are not focusing on the actual health issue that's plaguing the US today (poor diet leading to high insulin levels and poor metabolic health), they're simply loading Americans up with drugs that go after markers and symptoms.
To be fair, people brainwashed by the happy faces in the pharma ads probably go in expecting the doc to prescribe. And if he doesn't... Not happy. Look at the use of SSRIs in the US. Instead of working on your psyche, you take a pill that may damage your brain chemistry and be very hard to get off of. And patients expect to walk out with scripts.
This was right about the time of the housing bubble and as a contractor/home builder I knew that 99.9% of housing experts were wrong when they said prices would keep going up and people needed to buy now or get priced out forever. If not for every expert in my field being demonstrably wrong I may have not ever questioned that the majority of experts in other fields could also be wrong. It's pretty apparent in medicine though - we have drugs that are great at attacking risk factors for disease (i.e. statins) but debilitating chronic disease keeps going higher and higher. It's obvious medicine has gone off the rails... I want no part of it.
The housing bubble experience led me to question just about everything I thought to be true... I actually went through all my beliefs and examined the foundation for them. Some were sound, a lot were not (i.e. climate change). The takeaway is that very few people are able to question their beliefs, let alone change their minds when shown evidence to the contrary. Cognitive dissonance is real and people will rationalize just about anything to avoid it.
For me the lesson came with malpractice after I had AFib. The first care I got nearly killed me. That taught me a lesson: trust the signals your body is sending and don't settle for being shunted off on destructive meds for the rest of your life. Keep asking questions and fight back.
As a layperson, I wonder what the study would have shown had progesterone been used instead of progestin. But why would such a study even be attempted? There is no money to be made by marketing a compound that can't be patented...
This article is so on the money. And so applicable to our situation today.
The last thing I needed was another substack to follow, but this one seems irresistible.
+10 for the Gary Taubes citation.
You left out the elephant in the Women's Health Initiative study--all subjects received conjugated equine estrogen + progestin (IIRC the study was sponsored by Wyeth (clearly in hopes that their HRT product, Prempro, would get a boost from the study results, rather than being so dramatically shot down!)). To then generalize (as you have throughout your post) from equine conjugate to all HRT (and then writing as if all HRT is the same formula) is at best imprecise and at worst, sloppy. So I think your strong conclusion, despite all the impressive statistical analysis, misses a crucial point.
Even back in 2000, I thought equine conjugate was a bad idea because potential for immune system interactions. There are other HRT formulas: human recombinant estrogen, formulas using estriol, with or without progestin. Unfortunately, many of the alternative HRTs are compounded, with no large RCTs to guide clinical judgment.
Also, cardio-protection is not the only, nor from the user's standpoint, the most important, reason to choose HRT.
The 19-year re-analysis of the WHI found it had many many issues. For one, they forgot to control for women historically who had taken ER (estrogen therapy) in the placebo arm. Dr. Leon Speroff began early on showing the many issues with the WHI. Then Naftolin, the Yale statistician. Then my book, Safe Hormones, and then the 19-year re-analysis by 12 prestigious institutions, the very original authors of the first July 2002 published WHI findings, retracted their original study!!!! Their new reanlysis, 19 years later, hind site is better than foresight, found clearly that estrogen replacement (with Premarin in this case - ER., was statistically linked to a 23% reduced risk of getting breast cancer and a 44% reduced risk of fatality if you got this disease if you had taken estrogen. The new NIH 7 million medicare study is a retrospective observational study showing decreased all cause premature mortality if on ER, and a significant reduction of all five cancers (colorectal, lung, breast, ovarian and uterine) and only oral had increased risk of ischemic stroke and dementia while the other modes, especially vaginal, were CV and CA protective. None of the large European studies showed issues with HRT and in fact so much benefit that HRT is given for free in many countries to help protect their medical system as the hormones protect their citizens so much, such as Finland, Iceland, Wales, Scotland, italy, on and on and even Britain got in on this a year ago with a sliding fee schedule but free for those making much less money. Why? Socialized medicine and tracking their registries, like CV, CA and death registries, show such consistent benefit. It all depends on which science you are looking at. I have been on HRT for about 26 years a few years after I had breast cancer, almost 30 years ago now. And... going strong.
The following link is the textbook level of evidence based medicine. There is no way to put this politely. Almost nobody here is even at the textbook level of expertise in philosophy of medicine.
https://plato.stanford.edu/entries/medicine/#RandContTriaEvidBaseMedi
Sorry, now go read.
I was doing physics research in '84. We were never taught Evidence Based Medicine back then, but we limped along somehow without it. My research had implications for diagnosis in medicine.
Pulse oximeters use a similar technology, but in a different region of the infrared and at a simpler level.
My thesis didn't include any fancy statistics, but a couple of years after I published it, some journal editors asked me if I wanted the journal to retract an article that was very similar to my thesis work. That really surprised me.
My thesis defense committee profs asked my one question each. My answer for each was, "I don't know, but I'll look into it and get back to you." It turns out that that was the correct answer.
We all have blind spots. We all make mistakes. Game theory applies to research and always assume that data is cherry-picked until proven otherwise and that money drives research until proven otherwise. There are many ways to game research.
I appreciate your point but I'm afraid the example you chose to cite is a poor one. You were more correct on your first assertion. We've got 18 yr follow-up studies on HRT/MHT demonstrating that 20 yr study was poorly designed and newer studies found that women taking any type of HRT have a lower risk of heart disease, osteoporosis, diabetes, dementia, death, and also colon cancer, and other cancers as well. Women taking any type of HRT are less likely to die from breast cancer. It's assertions like these, based on old science, that contribute to millions of women not getting adequate treatment for menopause and unnecessary suffering. https://www.nhmenopausesociety.org/research/hormone-therapy-why-we-should-no-longer-be-afraid-of-the-breast-cancer-risk-says-new-literature-review/
A couple of points:
In spite of the flaws in the WHI study, as identified in previous comments, the conclusion of the article is correct - RCTs are the only way to prove medical efficacy over a large population. Could John have found a more valid RCT to support his thesis?
RCTs can be so flawed that their results are misleading and dangerous, as in the reported WHI study.
Studies which focus on mortality end points can leave out the real-world trade-offs between risk of death vs quality of life. We face such trade-offs every time we decide to travel or even to drive to the grocery store and, unfortunately, statistics will never give us a clear way to strike a balance.
Case in point: my wife has been on HRT for over 20 years, starting around menopause. ObGyn's often don't approve, as a result of the WHI study, and we have to pay for her HRT drugs because Kaiser won't. But the symptoms she has experienced any time she has gone off of HRT have been more than adequate to convince her to resume HRT. Fortunately, she has a trusted non-Kaiser health professional who is supportive of HRT. The balance is between the certainty of symptoms that make her miserable vs the possible (now largely discredited) increased risk of life-threatening disease.
It seems to me that any study like the WHI should at least document the difference in quality-of-life symptoms between the placebo and intervention arms of the study. Did WHI do this?
"RCTs are the only way to prove medical efficacy over a large population."
"What is lack of extrinsic validity for 400, Alex?"
There's no such thing as "bad cholesterol". In fact, there's no such thing as "high cholesterol". The idea that LDL causes heart disease is nonsense and I can't believe in this day and age that doctors still believe it.
Here's one of literally thousands of articles I could post showing there's no association between heart disease and "bad cholesterol".
https://drmalcolmkendrick.org/2017/03/20/cholesterol-lowering-proven-or-not/
This is an excellent review outlining a common foible in clinical intuition leading to observational research which is not yet science. HRT started in the 1950s when a cardiologist in Massachusetts noted that HRT not only relieved postmenopausal symptoms but seemed to lower the incidents of CVD and AMI among his patients. The rest is history. Your story omits the part where Wyeth (then Wyeth-Ayerst, then Pfizer) the manufacturers of Premarin (a proprietary mixture of estrogens actually extracted from horse urine) spent huge amounts on advertising to make certain this product dominated the market and was demanded by many women. It gained huge cultural acceptance. The large controlled randomized study you cite was necessary to break this advertising juggernaut.
You also omitted to note that while P/E HRT significantly increased the risk of breast cancer in women, Premarin and other E only HRT increased the risk of uterine cancer 500% more.
Thank you for pointing this out. It’s amazing how many people still don’t know how Premarin is sourced (look it up). Premarin named for: Pregnant Mare Urine. Of course horse urine estrogen isn’t healthy for human women! I don’t need any study to tell me that.
For all the women more concerned about HRT than maybe the overall point of this writing, I'm not seeing what type of HRT was administered. Premarin and estradiol are definitely different drugs. Within a few months of a hysterectomy, premarin caused deep indentations in nails and my hair continued to fall out in large amounts, for months after the surgery. A friend educated me about the horse urine used in the drug, the side affects and about plant based estrogen. The estradiol had no side affects (for 25 years). This is anecdotal and probably doesn't apply to a majority of women, but if you are in need of HRT for whatever reason, the information may be helpful.
I fully agree. Transdermal bioidentical estrogens plus progesterone and testosteone have been a godsend for me for the last 20 years (study n=1). Since the formula is compounded, it can be tweaked as necessary for best results.
For a comprehensive article and very lengthy annotated "links and references" section, see "Bioidentical Hormone Estrogen Prevents Heart Disease," March 15 2013, by Jeffrey Dach, MD.
https://jeffreydachmd.com/bioidentical-hormone-estrogen-prevents-heart-disease/
Also see Int J Pharm Compd. 2013 Jan-Feb;17(1):74-85.
https://pubmed.ncbi.nlm.nih.gov/23627249/
Abstract [excerpts:] "Conventional hormone replacement therapy results in increased thrombotic events, and an increased risk of breast cancer and dementia as evidenced in large prospective clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women's Health Initiative. A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors....
"Subjects receiving compounded transdermal bioidentical hormone therapy showed significant favorable changes in: Greene Climacteric Scale scores, Hamilton Anxiety Scale, Hamilton Depression Scale, Visual Analog Pain Scale, fasting glucose, fasting triglycerides, MMP-9, C-reactive Protein, fibrinogen, Factor VII, Factor VIII, Insulin-Like Growth Factor 1, and health outcomes of co-morbidities and a number of prescribed medications.
"Antithrombin III levels were significantly decreased at 36 months. All other measures did not exhibit significant effects. Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women. Cardiovascular biomarkers, inflammatory factors, immune signaling factors, and health outcomes were favorably impacted, despite very high life stress, and home and work strain in study subjects. The therapy did not adversely alter the net prothrombotic potential, and there were no associated adverse events."
Except that the same WHI group published research 15 years later showing that HRT has no impact on all-cause mortality at all. The 2002 study was flawed and caused much misery to women benefitting from but subsequently denied HRT. Scare-mongering like "HRT led to a nearly 50k women being harmed" needs to stop. doi:10.1001/jama.2017.11217
See my comment above. The '02 study was done on a single drug formulation, oral equine conjugate, which even at the time (when I was making my own HRT decisions with my MD) I thought was a bad formula (cross-species immune reactions, oral route through GI & liver, etc.). To generalize from one RCT to all HRT (as if all HRT is the same as Prempro) is not careful analysis.
Important points. Folks need to look past this 20 year old study and look at international guidelines based on newer and more robust analyses https://www.imsociety.org/wp-content/uploads/2020/08/2016-ims-hrt-health-recommendations-english.pdf
So true. While the WHI is a good example of how observational studies are flawed (HRT for everyone), it is also a good example of how RCTs can be flawed. As a result of the secondary analyses mentioned above and newer studies, the prevailing opinion among reproductive endocrinologists at least (if not internal medicine docs) is that in many women the benefits outweigh the risks if HRT is started early ie within 10 years of menopause. It is very effective for vasomotor symptoms and vaginal dryness (FDA approved indications) and "may" even decrease the risk of CVD (although not FDA-approved for that indication). HRT was also shown to decrease the risk of colon cancer in WHI, a finding that received relatively little attention in my opinion. I tend to prefer to prescribe FDA-approved bioidentical formulations (ie 17b-estradiol and micronized progesterone) although the data is out on whether or not they are in fact better or safer than synthetic hormones.
This, plus transdermal formulations and estriol as an alternative.
In many ways, the cholesterol hypothesis of heart disease provided the blue print for big pharma during the covid crisis. The heart attack ‘epidemic’ sweeping America during the 50’s was heavily promoted in the MSM but was almost certainly due to better technology for testing and changing disease classifications. Academics who disagreed with the cholesterol hypothesis were scapegoated, ridiculed and denied research funding. An expensive ‘antidote’ to heart disease (ie the various statins that have been manufactured over the years) was developed and given to a willing public.
Meanwhile, the evidence that over consumption of saturated and/or animal fats cause heart disease remain, 70 years later, ambiguous at best. The evidence that statins provide benefit to all but a sub-group of highly at-risk patients also remains stubbornly ambiguous. The safety profile of these drugs is certainly up for debate and not helped by clinical trial organisations (CTSU in Oxford, I’m looking at you!!) withholding accumulated safety data from the public
Wonder where we’ve seen all this happen over the last two years.......?
You nailed it.
Another great example that STILL is directing patient care erroneously is the observation that patients who get iodinated contrast may have increases in serum creatinine. Worse- it was conflated to iodinated contrast can cause not just creatinine rises, but renal failure. When a matched control study was done, it was found that the hospitalized patients who did NOT get iodinated contrast had the same amount of rise in serum creatinine that hospitalized patients who got iodinated contrast had. Iodinated contrast had no role in the creatinine rise. Yet, still, patients are refused the benefits of a CT scan with contrast because of this fallacy.
It is indeed complicated. Observational Studies can be biased. A single large RCT might be flawed, too. I think, here is some critique on that RCT: https://m.youtube.com/watch?v=DTCmprPCDqc&t=4210s
@1h22min
A couple items. First, all “studies” begin with a single observation. It’s the genesis, the seed, for an hypothesis then a testable theory. So observational studies are powerful in that they guide innovation. A serious problem with studies looking for statistical power is the systematic introduction of error that can dilute or eliminate real effects that are actually real as observed in the case study. This happens often when the suspected treatment agent is only effective when interacting with a second unidentified factor, or there is an unidentified factor responsible for the observation. Jumping to a parametric study will only find no effect and the discovery is lost. Second, in the HRT study the assumption that E reducing LDLs as the mechanism reducing cardiovascular events is errant leading to the finding of no effect in the parametric study. Many studies have shown that cholesterol is not the relevant factor in CVD, the relevant factor is vascular inflammation. In fact, the relevant variable in the study mentioned is actually vitamin D status and its effects on reducing inflammation hence CVD. So, while E is a minor agonist of vitD, the heavy lifting with respect to CVD was vitD. So here we have that second unidentified, unappreciated, ignored? variable that is responsible for the observed effect. Don’t get me started on why vitD, a free, safe, readily available agent is systematically villified/ignored by the medical community. I think it has something to do with $$$.
John I wish you expand your thoughts with regard to two issues: (1) you are emphasizing relative risks rather than absolute risk increases; these absolute risk increases seem small per woman, and (2) women take HRT for a reason and place some value on the benefits received. Shouldn't those values be formally traded off against the (small) absolute risk increases? As an aside I'd like to see us de-emphasize the multiplication of risk by some population size, and concentrate on what the risk is per-person.
And for most women (myself included) on HRT, cardioprotection is low on the list of reasons they chose HRT in the first place.
the 2002 JAMA study cited actually concludes there was no difference in all-cause mortality, suggesting absolute risks around one very big indicator--death--were not different between the groups studied.
But be careful as "were not different" is different from "demonstrating equality of mortality incidence".
Ok, but still referencing old study/findings. IMS summarizes new analyses:
Key points
-In women under age 60 and recently postmenopausal with no evidence of cardiovascular disease, the initiation of estrogen-alone therapy reduces coronary heart disease (CHD) and all-cause mortality [A]
-Data on daily continuous combined estrogen–progestin are less robust but other combined therapy regimens appear to be protective as shown in Danish and Finnish studies [A]
-Recent meta-analyses and WHI 13-year follow-up data all show a consistent reduction in all-cause mortality for MHT users [A]
-It is not recommended to initiate MHT beyond age 60 years solely for primary prevention of CHD [A]
https://www.imsociety.org/statements/ims-recommendations/
Good points. The absolute risk increase IS small for women on HRT. Some women benefit a lot from HRT but now have to endure browbeating at every checkup, lectures about heart disease, stroke etc. HRT can improve sleep when menopausal symptoms cause wakefulness; one of my sisters, a very fit retired Navy vet, says she's willing to take her chances on the hormones because without them life is hell due to insomnia from hot flashes. I know women who've been cut off cold turkey by overzealous obgyns, a pretty destructive move. Individual health and low absolute individual risk have to be considered and weighed, and the patient educated.
Choose your PCP to have the same philosophy about HRT as you do--it makes life much easier after menopause.
Angel Dust?
wouldn't touch the stuff, lol
The risk is not as small for perimenopausal women as for post-menopausal women, iirc. So grouping all women together lends itself to Simpson's Paradox.
Thank you. We are training doctors to practice population-based medicine and to worship EBM & algorithms, and we are not attracting critical thinkers to medicine. As a result, we will see more people turning to naturopaths and chiropractors for care. We deserve the loss of trust we are experiencing. Unfortunately, medical schools seem to be embracing the corporate and communist takeover (what do we call that, when the communists are taking over the corporations?).
I hear that leading med schools are now recruiting at the Ape Cage at zoos.
This is the perfect description for what's happening.
Fifteen years ago my health (at 42) was headed in the wrong direction. I was overweight, my eyesight was bad, I had hand tremors and had recently diagnosed with asthma. My doctor put me on an inhaler to help with the asthma and he told me I'd need it for the rest of my life and the dosage would increase as my asthma progressed. I did it his way for a month and gained 10 lbs due to the steroids in the medication. I then did my own research, did a simple diet change (low carb) and my asthma disappeared almost overnight. Additionally I lost 40 lbs, my hand tremors disappeared and my eyesight improved to the point where I no longer need glasses. How many people out there can say that their eyesight got better as they got older?
I'm 57 today and after 15 years of much reading I now know that doctors are not focusing on the actual health issue that's plaguing the US today (poor diet leading to high insulin levels and poor metabolic health), they're simply loading Americans up with drugs that go after markers and symptoms.
I'll never go back.
To be fair, people brainwashed by the happy faces in the pharma ads probably go in expecting the doc to prescribe. And if he doesn't... Not happy. Look at the use of SSRIs in the US. Instead of working on your psyche, you take a pill that may damage your brain chemistry and be very hard to get off of. And patients expect to walk out with scripts.
I know, I was one of those people.
This was right about the time of the housing bubble and as a contractor/home builder I knew that 99.9% of housing experts were wrong when they said prices would keep going up and people needed to buy now or get priced out forever. If not for every expert in my field being demonstrably wrong I may have not ever questioned that the majority of experts in other fields could also be wrong. It's pretty apparent in medicine though - we have drugs that are great at attacking risk factors for disease (i.e. statins) but debilitating chronic disease keeps going higher and higher. It's obvious medicine has gone off the rails... I want no part of it.
The housing bubble experience led me to question just about everything I thought to be true... I actually went through all my beliefs and examined the foundation for them. Some were sound, a lot were not (i.e. climate change). The takeaway is that very few people are able to question their beliefs, let alone change their minds when shown evidence to the contrary. Cognitive dissonance is real and people will rationalize just about anything to avoid it.
For me the lesson came with malpractice after I had AFib. The first care I got nearly killed me. That taught me a lesson: trust the signals your body is sending and don't settle for being shunted off on destructive meds for the rest of your life. Keep asking questions and fight back.
I'm a lifelong asthmatic and found the Albuterol and steroid inhalers made life unbearable. Insomnia, aggressiveness, palpitations.
I'm fine now without any asthma meds, just use common sense and avoid allergens.