Peter Attia - JoAnn Manson

1) JoAnn Manson introduces the concept of H-index to the audience, a metric used to calculate the number of publications that have been highly cited. He mentions that JoAnn Manson, one of the guests, has an impressive H-index of 305, which is rare in the field of biomedical science. Moving on to discuss the Women's Health Initiative study, Manson explains how observational studies led to experiments to test the effectiveness of hormone therapy in preventing heart disease, cognitive decline, and other chronic diseases. These experiments were launched in the early 1990s to determine if hormone therapy's prescription was valid for preventing chronic diseases in menopausal women.

2) JoAnn discusses the Women's Health Initiative and their aim to test the use of hormone replacement therapy for the prevention of chronic diseases like heart disease, stroke, and cognitive decline. The healthy user bias was a significant factor that had to be controlled as it could haveled to an over estimation of the benefits of hormone replacement therapy. The common formulations used for hormone replacement therapy were conjugated estrogen with and without medroxyprogesterone acetate, which were found to have promising results in observational studies. However, the randomized clinical trial was crucial to determine causality and to ensure the safety and effectiveness of hormone replacement therapy. The study also revealed important biological differences between women in early menopause and those in later menopause.

3) One theory is that a pharmaceutical company that developed conjugated estrogens became the dominant force in hormone therapy, and the synthesis process for estradiol from plants only gained traction in recent decades. The inclusion and exclusion criteria for the Women's Health Initiative (WHI) study are also discussed, with particular emphasis on the misconception that women who had hot flashes were excluded from the study. The conversation covers the exclusion criteria, including prior history of cancers, cardiovascular events, and the inclusion of women with a broad range of bone health issues.

4) The criteria for enrollment in the Women's Health Initiative study were discussed. Women between the ages of 50 and 79 were included, with no exclusion based on the length of time since menopause. Some women had previous hormone therapy use but were not excluded. The primary outcomes of the study were coronary heart disease and breast cancer, with coronary events being the main focus and the trial being powered to detect a difference favorable to heart disease.

5) JoAnn discuss the use of lipid lowering therapies and oral estrogen in the early to mid-90s during the Women's Health Initiative study. In the study, only 7% of the population was taking statins at the start of the study, but that number increased to over 25% during the intervention phase and even higher with longer follow-up. As for oral estrogen, it was known at the time that it increases the synthesis of clotting proteins, leading to an increased risk of thrombosis. They also discuss their personal hypotheses going into the study, with one believing that women in early menopause transitioning from having their natural pre-menopausal estrogen exposure could benefit from starting estrogen early on in terms of risk factor status and dilating blood vessels to the heart.

6) JoAnn discusses their initial skepticism regarding the magnitude of risk reductions seen in observational studies on the benefits of hormone replacement therapy (HRT) in reducing heart disease. They also address the common assumption that estrogen causes breast cancer and how it was surprising to find that no increased risk of breast cancer was seen with estrogen alone, while there was an increased risk with estrogen plus progestin. He explains that uniform surveillance for breast cancer with mammograms was required every year to properly examine this question in a randomized clinical trial. Overall, the study found a reduction in breast cancer close to 20% with conjugated estrogen in longer follow-up.

7) JoAnn highlights the difference between relative risk and absolute risk as it pertained to the Women's Health Initiative (WHI) study on hormone replacement therapy (HRT). The study was halted prematurely, and the headline was "estrogen causes breast cancer," leading to a reduction in HRT use despite it being an FDA-approved treatment for hot flashes and night sweats in women in early menopause. The absolute risk increase in breast cancer was only 0.1%, or one extra case per thousand women, during the 5.2 year period, and the extrapolation of the findings to all women taking HRT for various reasons was inappropriate.

8) JoAnn discusses the enduring legacy of the Women's Health Initiative (WHI) study, which is that hormone replacement therapy (HRT) is synonymous with breast cancer. However, two significant inaccuracies arise from this legacy. Firstly, the study suggests that estrogen is not the cause of breast cancer but that MPA is. Secondly, the study only found an increase in breast cancer incidence of one case per thousand, with no difference in mortality. Despite this, it seems that most physicians and patients contemplating HRT are not aware of these details. The focus of the discussion is on the outcomes of the WHI study, including the risks of breast cancer and the benefits of symptom relief.

9) JoAnn discusses the swinging perception of hormone therapy throughout the 1980s, 90s, and early 2000s, and how the pendulum is now coming to rest in a more appropriate place. The best candidates for hormone therapy are women in early menopause who are in good health and have moderate to severe hot flashes and night sweats. The speaker calculates that somewhere between four and five million women missed out on HRT in the last 22-23 years, which saved around 4,500 cases of breast cancer. HRT has also reduced the incidence of hip fracture by about 1.5%. However, the benefits of bone health are short-lived, and treating women from early menopause to their 70s or 80s is not a good idea as it leads to increased breast cancer risk.

10) JoAnn discusses the results of the Women's Health Initiative study on hormone replacement therapy (HRT) and how it can affect women's health. The study showed that the use of HRT can have favorable outcomes for women in early menopause, whereas it can have a bit of a signal in age 70-79, where estrogen alone may be linked to a small increase in mortality risk. There have been concerns over the risks of HRT, as the Whi study showed an increased risk of stroke with both estrogen alone and estrogen plus progestin, as well as cognitive decline among women 65 and older.

11) JoAnn discusses the current trends in hormone replacement therapy (HRT) and how they differ from the drugs that were tested in the Women’s Health Initiative (WHI) study. The current formulations of HRT include transdermal estradiol and micronized progesterone, which are deemed safer by healthcare professionals. Although more randomized trials of these formulations are needed, mounting a large-scale trial like the WHI would be extremely expensive. She acknowledges that the WHI did put an end to unfavorable HRT practices, but it was over-extrapolated to women in early menopause seeking treatment for hot flashes and night sweats.

12) JoAnn discusses the importance of women taking their menopausal symptoms seriously and finding a clinician who will do the same. The North American Menopause Society's website provides a "Find a Certified Menopause Practitioner" tab for women to locate clinicians with expertise in menopause management and hormone therapy. The speakers also touch on the lost generation of women who were denied HRT due to the ignorance of their physicians and the media's irresponsibility. They also applaud the speaker for acknowledging the limitations of the Women's Health Initiative and speaking out on this issue.