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I watched my older sister go through menopause and witnessed the nightmare roller coaster ride she took. I swore I would not go through that. Three months after my last menstruation (15 years ago) I immediately got bioidentical hormone replacement. E2, E3 & progesterone. I’m sailing through menopause with none of the typical symptoms, not even a hot flash. My hormone levels are tested annually. My heart is great and my bones are great. Just sayin…

Were those clinical trials above only on synthetic hormones. I wonder if a comparison has been done on synthetic vs bio identical.

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Women’s health and heathy aging need a lot more research to assess what really benefits individuals. For now, I will continue my estrogen, exercise and “food is medicine” approach.

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Conspiracy theorist Dr. Andrew Huff, former VP of Ecohealth Alliance, claims that NIH funded development of SARS-COV-2.

https://myemail.constantcontact.com/EcoHealth-Alliance-Newsletter.html?soid=1109104170770&aid=B8ZzloGYn_A

Clearly, Dr. Huff couldn't have known anything about what happened at the Wuhan lab. He's a conspiracy theorist. /sarc

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"A former vice president for the EcoHealth Alliance, a major funder of the Wuhan Institute of Virology, claims that his organization "developed" SARS-CoV-2 through gain-of-function research that makes viruses more dangerous."

https://justthenews.com/government/federal-agencies/former-ecohealth-alliance-vp-says-fauci-funded-group-developed-covid-19

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Here's evidence that the allegation of smearing of hydroxychloroquine by the FDA is a conspiracy theory.

"FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems"

https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or

It's irrelevant that primary care providers and rheumatologists have prescribed hydroxychloroquine for millions of people as outpatients, taking billions of doses for _years_, including people with heart disease.

Somehow taking HCQ for five days at clinical dosing is dangerous in the context of covid for people without heart disease as outpatients, when it's not dangerous for people with heart disease outside of the covid context (e.g., for lupus or rheumatoid arthritis) to take HCQ as outpatients for years, according to the FDA. And we know that the FDA can be trusted to be reliable and competent.

So, clearly, the allegation that the FDA smeared hydroxychloroquine is a conspiracy theory.

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Sorry, I cringe when I see comments like this:

"Recently, the FDA commissioned a pilot project: RCT-DUPLICATE to do just this. Sadly, the result was suboptimal. Less than 50% of RCTs could be reliably emulated or replicated with this design. More work is needed."

- Without numerous details, the 50% is worse than meaningless: It's a misleading expression of overconfidence in a single and arbitrary number. What criterion was used to draw such a sharp distinction between "reliable emulation" (or replication) and not? I saw no clue here or in the linked Endpoints article.

This much I'll wager: The 50% claim is one that could be shifted all over the place by changing the criteria and analysis in defensible ways. The "more work needed" is to fight dichotomania - the compulsion to reduce continuous phenomena to arbitrary dichotomies - and to stop quoting unclear and degraded summaries as if they were revealed methodologic facts. In this case the most pressing need is to provide instead more informative summaries, such as interval estimates from emulations plotted or tabulated in detail against those from the corresponding RCTs, and direct interval estimates of the differences between the studies.

Also needed is recognition that the RCTs are not the gold standard they are treated as: Their selective enrollment guarantees that they won't be estimating the same effect as what will be seen in practice when patients are no longer carefully cherry picked to avoid adverse events and experience benefits. RCTs can and often suffer their own biases due to post-randomization withdrawals, lack of masking (blinding), and misanalyses. These problems mean that emulation meta-studies are only looking at associations of select observational analyses with trials. Those associations will be far from perfect, not only from bias and errors in both the observational data and the trials, but also from real differences in the effects or questions being targeted.

Yes, statistical adjustments for these heterogeneity sources can and should be made to the extent that the sources were measured in the studies. But, for guiding practice, even the best statistical analyses cannot by themselves tell us whether a disagreement reflects shortcomings of the emulations or of the trials or both. That is a question about what caused the disagreement, and as such requires causal assumptions that are best made explicit and realistic, rather than hidden or simplistic (like assuming the RCT is giving the "right" answer). And when more credible assumptions are made, I'll wager again that the measurement and adjustments are far from sufficient to enable any declaration remotely approaching the certainty reflected in "less than 50% of RCTs could be reliably emulated or replicated with this design". Rather, the latter kind of statement reflects the primitive state of meta-research reporting (and I fear, conduct) outside of the most advanced methodologic literature.

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September 24, 2022
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Thanks Sarah for the comment.

In case it's not obvious, my view of target-trial emulation (TTE) is essentially the same as that detailed by Dr. Gopalakrishnan. I have written to Zachary Brennan (the author of the May 2022 Endpoints article that Vinay cited) for further information about RCT-DUPLICATE.

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I was a staff scientist on RCT DUPLICATE for part of the project as the PI s were from my research group at BWH (it was funded by FDA) ...please see the article below on the first results that detail the methods including agreement metrics.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.051718

Maybe in a future post I will dive more into the details of RCT DUPLICATE and also talk about my dissertation work which is somewhat related to it

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Thanks! I hope you post more about RCT DUPLICATE and dispel any mischaracterization of its results. The Circulation paper you linked has a great team of authors and their presentation is informative. From the abstract: "The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled... Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation... Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly."

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This article is the perfect example of what I was hoping to find in the Sensible Medicine substack! Dr Mandrola wrote an interesting article, others had salient comments, and there was a good discussion. And I gained new insights.

Well done!

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For me, the best part of this post was Dr. Mandrola's suggestion that all studies should have an expiration date. Am always astonished that many relatively ancient RCTs and analyses are still widely cited, and are staunchly believed to be the final law-giver in this or that domain. No matter that experts like Dr. Mandrola and Dr. Prasad frequently point out that reversals of medical protocols occur regularly. Wish that there were more - would be an indicator of an alert and ever-curious medical sector.

Most readers are probably too young to remember the super-hyped 'Feminine Forever' marketing wave. It shocked me then, and still resonates. My own view on HRT is simply that no potent treatment should ever be given anyone UNLESS the omission of that treatment clearly puts the patient in serious danger. But of course, as with liposuctions, botox, cosmetic surgery, and so many other elective interventions, it seems that societal pressure and marketing prowess rule the day.

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Bravo David Allely! You have provided the best summary and accurate analysis of WHI. And you’re not even an MD yet. Thank you. ERT started prior to menopause in a woman with total hysterectomy has many benefits. WHI was poorly interpreted at the time.

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I remember when I turned 50 in 1999 and my PCP said I had to go on HRT to prevent a heart attack and I declined saying I would rather die suddenly from a heart attack than suffer from breast cancer. She informed me the insurance company would ding her if I refused. I said take the hit for me and mark I adamantly refused, was thankful I did when the 2002 study halted this push on women with so symptoms or other benefit. 73 now and heart healthy but still needing ultrasounds every year after each 3 D mammogram,

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It's important to understand the opposing side's position. Consequently, I have tried to wrap my head around the HCQ-skeptic position. Here is what it seems to be.

1. Primary care providers typically have problems with followup. They may not see negative outcomes. Physicians whose patients are in hospitals have a better opportunity to see negative outcomes (hospitalization, death, chronic morbidity caused by covid).

2. Mild covid is difficult to diagnose because of viral respiratory disease confounders which have similar symptoms (flu, syncitial virus, etc.); PCR shows exposure, not necessarily active disease; do PCPs really do lung scans or lab work to nail down the diagnosis; hence, what are they actually treating with HCQ???

3. I have tried HCQ on my (hospitalized) patients and it doesn't work. They still died. [No, I am not a physician. I am imagining what a physician HCQ-skeptic would find compelling.]

4. There is no compelling RCT proof that HCQ works anywhere. [There is controversy here, of course.]

5. HCQ was pushed because of politics. [More like the skeptical position was political in nature, but this is what some HCQ skeptics _feel_.]

Have I missed anything in the HCQ-skeptic position? Please enlighten me.

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When they take a natural substance and alter it so that it can be patented and then think it will have the same effect on the human body as the natural substance does, it is a mistake. Unfortunately the studies seem to not understand that estrogen from horse urine is not the same and has components that human estrogen does not. A study on bio identical hormones might show very different results. The fact that this is never mentioned is a typical example of misleading science.

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Read Sex, Lies and E. It's a good read on exactly what you are saying here. Bioidentical hormone replacement is healthful.

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So true and I'm commenting again on this matter because of the awful affects I suffered from Premarin after a hysterectomy. Estradiol is a very different drug, cheap, plant derived and did not cause my hair to fall out or ridges in all my nails, like Premarin did. I took Estradiol for over 25 years and stopped when I would likely have gone through menopause, though a doctor had warned me that I was sure to have a heart attack/stroke/cancer earlier (based on very little information). I believe there is one study on Estradiol from the early 90s, maybe USC, but haven't been able to find it. Will never forget talking to a woman who had taken premarin for some years, trying not to stare at her scalp through her very thin hair, and her insisting she had never had any adverse side affects from it. Sad.

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Read Sex, Lies and Menopause. It's a good read on the benefits of bioidentical hormone replacement.

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These comments are great! I like them better than the posts.

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Keep the drugs with NNTT ~= 1 (NNTT = "Number Needed to Treat to get the endpoint benefit")

Pitch the rest

NB

Assuming competency in primary care (e.g., Brian Tyson and George Fareed of El Centro Clinic in Califormia and a few dozen others around the US and outside it), HCQ is a parachute for high risk covid patients when used to treat patients within 72 hours of symptom onset--treatment is based on suspicion, with lab work and lung scans being used to provide additional evidence to support the diagnosis based on suspicion. (This is exactly the protocol that the CDC recommends for high risk influenza patients--treat early with antivirals based on suspicion, so it's hardly revolutionary.)

Black Swan Challenge I (for early treatment of covid with HCQ)

Find one primary care physician who has tried treating high risk covid patients with HCQ early and has discontinued it and says it doesn't work. I have been looking since May 2020 for one and no black swans have yet been sighted. (No, hospital physicians don't count. They treat _late_ because they see patients _late_, after covid has already progressed.)

Black Swan Challenge II (to support the proposition that HCQ is dangerous for cardiac patients)

Find me one rheumatologist who won't prescribe HCQ for his or her patients with heart disease. Or find me one PCP whose patient(s) have died from heart failure while being treated for covid with HCQ.

So, anonymous MD, MPH, MAH, I may not be a clinician but I sure as hell try to understand their point of view. (MAH = "Master of Ad Hominem")

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less pills, and life is less complicated.

in 2013 I moved both of my parents, age 88 closer to my home after mom's stroke

I then, took them to my wonderful doctor Dr Fletcher, and we worked to get mom off of half of her meds that were piled on her by various doctors. Then, I took dad to Dr Ujevic and did the same.

Mom lived to 2016 and died of natural causes. Daddy is 98 and still going steady.

I have learned a lot over the years from taking care of my peeps

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The bar should be high when "treating" otherwise healthy people with pharmaceutical drugs. Trying to work against the body's genetic programming and natural design is hubris. Menopause is there for a reason. So we don't get pregnant at 65! Reminds me of Fosamax. My mom was was told she should take both hormones and Fosamax. Thank goodness she doesn't fall for that stuff. She is "non-compliant". It seems there is a new push for hormones in the media.

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There is some biological concept missed here. It's not so we don't get pregnant that hormones drop. It's that as we age and our fertility is less effective to our species...our hormones begin to drop as a form of programmed cell death. As we age and produce less effectively, we aren't useful...so we must die...be it heart disease, cancer, strike, osteoporosis, Alzheimer's. Read Sex Lies and Menopause. There is a good case for bioidentical hormone replacement. If we mimick the health we received from "good" hormone levels when we are young, our health remains. If you step back and think anthropologically and biologically you may have a new appreciation for HRT through biological replacement, not pharmas replacement with synthetic hormones.. synthetic hormones have a negative effect on our health... because they are synthetic. Most medical doctors may not be aware of the bioidentical hormones, unfortunately. The more we live in harmony with nature, including rhythmically living in hormonal balance the better our health is. Our hormones run a lot of life. So losing and dropping hormone levels can slowly kill you. It's done by design.

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It seems we are talking at cross purposes. I wish you the best.

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Out of curiosity, I checked Wikipedia on T.S. Wiley, the author of Sex, Lies and Menopause.

Apparently, she runs a business selling her 'Wiley Protocol' to people in the pharmaceutical branch.

Also, there appear to be some serious questions about her qualifications and honesty. Following are extracts from Wikipedia.

"Wiley wrote a second book, Sex, Lies and Menopause, in which she claims that hormone imbalances cause many age-related diseases, and these imbalances are caused by humans straying from "natural" rhythms of light, seasonal eating and child birth. Wiley claims that mimicking the levels and cycles of estrogen and progesterone found in a 20-year-old woman will prevent or treat age-related diseases.[2] Subsequent to the book's publication, this hormone regimen became known as the "Wiley protocol" and Wiley created a pharmaceutical compounding program that pharmacists could contract into, stipulating compounding methods, materials, testing, packaging and recommended pricing in exchange for Wiley's company providing the packaging materials bearing the Wiley protocol's trademark."

"Former actress Suzanne Somers advocates the Wiley Protocol in her book Ageless: The Naked Truth About Bioidentical Hormones.[6]"

"Controversy

Wiley has been criticized for promoting her version of BHRT without proper qualifications or scientific evidence. On October 11, 2006, Erika Schwartz, Diana Schwarzbein, and five other MDs who have worked with BHRT during their careers issued a public letter to Suzanne Somers and her publisher, Crown, criticizing Somers' endorsement of Wiley's protocol. In the letter they alleged that the Wiley Protocol is "scientifically unproven and dangerous" and that Wiley has no medical or clinical qualifications;[7][8] other criticisms of the protocol itself have stated that the levels of hormone are dangerously high.[9][10] Wiley has claimed on her website and in speaking engagements that she earned a B.A. in anthropology from Webster University in 1975. On November 27, 2006, Newsweek reported that Webster has no record of this degree.[11] Wiley's bio page was then changed to "Pending B.A. in Anthropology, Webster University, 1975" and then again to "Attended the B.A. Program in Anthropology, Webster University, 1970-1975". ABC News reported on February 16, 2007, that, according to Webster, she received only a blank diploma.[11]"

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There are other books supporting the concepts proposed in her book. I use a compunding pharmacy and don't know the specifics of her "pharmacy" connections. I read the book and the the studies cited in the book are there for any one to review (although post pandemic I have less and less faith in science). She does explain a lot of how science has made policies based on poor science (statins, our food pyramid, etc etc...the concepts that drive medicine even to this day). I guess what resonates with me is the theory of how our biology with nature changes and why. And through mimicking natural rhythms provides health. I guess it biologically makes sense, and intuitively makes sense. And through this pandemic, I also trust when wiki posts their view of the world. Of course there may be controversy as she is going against mainstream medicine which pharma has made money off of (synthetic hormones, statins etc). We all need to be educated, I just offered another view of the topic for anyone or read and make a decision for themselves about the theory, data etc. She is controversial. Listen to any podcast or interview she is in. She feels strongly about the concepts and being against mainstream is not an easy place to be. Again we have seen this in the pandemic for sure. I am not an absolutist or a medical doctor. I do appreciate differing views.

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I would say not cross purposes. I agree with a lot of your sentiment. Just another perspective about why hormones fall off as we age beyond so we don't get pregnant. I am a less is more person as far as medical intervention goes. Mother nature has worked for a long long time. She is pretty brilliant.

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