A Case for Oral (Estradiol)

It feels a bit like I’m part of a small fetish group, one where we talk about our weird preferences behind closed doors because we’re sure that nobody else will share our enjoyment of wearing furry animal costumes or sucking on toes.  But, instead of furries and feet fetishes, I have an oral estradiol fetish  But, before you shun me and toss me out of your polite society of hormone specialists, let me explain. 

In 2002, the Women’s Health Initiative came out, scaring women around the world by telling them that HRT was giving them breast cancer, heart disease, strokes, and dementia.  Oh, and don’t forget about the blood clots.  So, more than 80% of women taking HRT abruptly stopped it.   

Throughout the subsequent years, we realized that many of the harmful effects seen in the WHI were due to the synthetic oral progestin they’d used (medroxyprogesterone acetate, or MPA), and some of the side effects were because we were giving an oral synthetic estrogen (Premarin, aka conjugated equine estrogen, CEE).  For example, both CEE and MPA increase the risk of blood clots, and women in the WHI who were on these hormones had twice the blood clot risk as their hormone-free peers.  We also saw an increase in heart attacks and strokes in late-starters (women starting HRT > 10 years from menopause onset) within the first two years of starting hormones. The take-home message, after the dust had settled, seemed to be that oral estrogen and oral progestins are dangerous.  

During that same time, we started seeing an uptick in the doctors prescribing a much safer form of estrogen - transdermal estradiol.  Transdermal options include patches, gels, and creams. Multiple studies have found no increased risk of blood clots (VTE or PE) or heart attacks/strokes with transdermal estradiol.   In the ESTHER study, we saw that even people with known clotting disease and/or previous clots didn’t have an increased risk of future clots when taking transdermal estradiol.  

Two things to understand about transdermal estradiol:

One:  It is incredibly safe.  There’s no doubt that it’s the safest form of estrogen.  If safety is your only concern, you can stop reading now because transdermal estradiol wins hands-down.  Part of this safety comes from the fact that when you take a hormone through the skin (vs the mouth), you bypass the liver.  When you bypass the liver, the liver doesn’t get involved in metabolizing the hormone.  In the case of estradiol, the involvement of the liver in metabolizing the oral version is responsible for some of the perceived adverse side effects, such as oral estrogen leading to a higher SHBG (serum hormone binding globulin) level or oral estrogen occasionally causing CRP (C-reactive protein) to go up.  Or, in the case of blood clotting, oral estrogen causing activation of the clotting cascade.  None of these things happen with transdermal estradiol because it doesn’t go through the liver.  

Two: Transdermal estradiol is bioidentical.  Unlike the synthetic oral estrogens used in the WHI (as well as multiple other previous studies), the estrogen in transdermal estradiol has the same chemical structure as the estradiol your body makes.  Premarin (CEE) is comprised of several estrogens, including estrone and a slurry of other non-bioidentical estrogens.  Many of the side effects and problems we saw in the WHI and other studies happened not because Premarin was taken orally but because it was a non-bioidentical form of estrogen taken orally.  

Water or Antibiotics? 

So if transdermal estradiol is the safest form of estrogen, why are we still talking?  In this case, I’d argue that the safest option isn’t the best for most people.  Let’s take a real-world example.  Let’s say you have bacterial pneumonia.  You have the option of taking water by itself or taking water with antibiotics.  The first option is the safest.  It is not going to cause a side effect or allergic reaction.  It will not send you to the hospital because of a rare side effect.  And, while water won’t be as good at fighting your bacterial infection as antibiotics, there’s no denying that staying hydrated is good for your health.  So, you should just take the water, right?  It’s the safest option, so it must be the best option.  

Wrong.  Most people would agree that you’d be better off taking the water with antibiotics vs water alone, even though there’s some risk to taking antibiotics.  Why?  Because you have to look at not just the safety of a therapy but also the benefits.  The risk-benefit ratio is better for the water plus antibiotics than for the water alone.  

The same can be said about transdermal estradiol vs oral estradiol.  Transdermal is absolutely the safest.  But, it has fewer benefits than oral estradiol, so it is not my first choice for most women. Namely:  Oral estradiol is (likely) better for reducing cardiovascular disease risk than transdermal estradiol.  

Cardiovascular Disease Risk

We have decades' worth of studies that tell us that, when started early (within 6-10 years of menopause onset), oral estrogen reduces your risk of cardiovascular disease (CVD).  Know that when I say “estrogen,” I am referring to all estrogens, synthetic and bioidentical.  When I say “estradiol,” I’m referring to bioidentical estradiol.  

In one of my favorite review articles about estrogen and CV disease (Hodis, 2022), the author notes that “more than 40 observational studies show a consistent 30-50% reduction in CHD (coronary heart disease) in HRT users vs nonusers” and that the 23 RCT’s (randomized controlled trials) that gave estrogen to young (< age 60), healthy women have shown similar reductions in both CHD and mortality rates (30-50% reductions).  A meta-analysis by the Cochrane Group (Boardman, 2015)  similarly found a reduction in mortality rates of 30% and a reduction in CHD of 48% when HRT was started within 10 years from menopause onset.  

The idea that estrogen therapy works to prevent plaque accumulation in young, healthy women but doesn’t reduce CHD risk in late-starters or women with established atherosclerosis is called the “Healthy Endothelium Hypothesis” or the “Timing Hypothesis.”  For estrogen to have a positive impact on preventing plaque accumulation, you must have a healthy endothelium (that’s the inside lining of your blood vessels).  We have several human and animal studies that support the idea of the Timing Hypothesis, and this is not something we argue about anymore.  When it comes to preventing CHD in women with HRT, timing is everything.  

Okay, so we know that estrogen when started early in women without current atherosclerosis, can reduce the risk of future CHD by 30-50%.  We know this from >50 human studies and we have support for the Healthy Endothelium Hypothesis across multiple animal species, including rabbits, rats, mice, and non-human primates.  

Let’s just give transdermal estradiol! 

We have all of this evidence that estrogen can prevent CHD. Still, we also know that oral estrogen can increase blood clot risk and may have other less-than-ideal effects on estrone, SHBG, and CRP levels. Hence, it makes sense that we’d just substitute the oral estrogens used in these studies and give transdermal estradiol, right?  

We have little evidence that transdermal estradiol has the same cardiovascular disease benefits as oral estrogens. But, we all agree that oral synthetic estrogens (CEE or Premarin) are too rife with side effects and risks to be our go-to estrogen.  What about oral estradiol?  Although it requires metabolism by the liver, it is bioidentical, so it doesn’t have the same problems associated with CEE.   Most of the studies discussed above used oral synthetic estrogen (CEE), but a few used oral estradiol, and the results were impressive.  

Randomized Controlled Trials (RCTs) on bioidentical estradiol: 

Let’s look at the randomized controlled trials, RCTs, (the gold standard for clinical research) that used oral and/or transdermal estradiol (vs their synthetic evil twin).  The ELITE study found that oral estradiol 1 mg daily given to healthy women within 6 years of menopause onset was associated with less progression of subclinical atherosclerosis (measured by CIMT) compared to placebo. In the EPAT study, the findings were the same:  the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking oral estradiol (1 mg) than in the placebo group.  Finally, the Danish Osteoporosis Study (DOPS), a 16-year study of healthy women, found that ten years of oral estradiol 2 mg daily was associated with significantly reduced risks of heart attacks, heart failure, and death (HR 0.48, primary composite endpoint).  

TLDR:  We have three RCTs that gave healthy, early menopausal women between 1-2 mg of oral estradiol and saw a reduced risk of cardiovascular disease.  

What about studies on transdermal estradiol and CV disease?  

Unfortunately, the studies are sparse.  The only RCT study we have looking at transdermal estradiol (E2) for CV disease is the KEEPS study (Menopause, 2019), where they gave either low-dose transdermal E2 (50 ug) or low-dose CEE (0.45 mg oral) to healthy women within three years of menopause onset.  They saw no change in CIMT plaque progression in either group compared to the control group.  

There are a handful of other non-RCTs that used transdermal estradiol. Still, the results from these are challenging to interpret in many cases because the number of women using transdermal (vs oral) estradiol was so much lower. The results are all over the map.  

For example, Chilvers, 2003 (case-control study) looked at 864 women with acute MI and matched them to community controls. They found oral estradiol was associated with a reduced rate of acute MI (myocardial infarction) with an odds ratio (OR) of 0.80. In contrast, transdermal E2 was associated with an increased risk of MI (OR 1.7), but there were only two cases where transdermal E2 was used.  

In another study (Lokkegaard, 2008), a cohort study of 600,000+ Danish women, they found that oral E2 use was associated with an RR (relative risk) of MI of 0.98 and transdermal E2 had an RR of 0.62 compared to no-hormones.  This may make you think - “See, transdermal E2 IS good for reducing CV disease!” But … a) this wasn’t an RCT, the gold standard of studies, and b) the transdermal E2 group was 1/0th the size of the oral E2 group, so it’s hard to know what to make of these results.  

Varas-Lorenzo's (2000) a case-control study, found that oral CEE and transdermal E2 were associated with a similar protective effect on CHD. However, the transdermal E2 group made up only 20% of the total group of HRT users, so, again, it’s hard to hang our hats on these results.  

All of this is to say that while transdermal estradiol MAY reduce CHD we really don’t have the evidence to say that yet.  We also have reasons to believe that it may not because we know that lipids are a crucial driver of CHD and that oral estrogens (CEE and estradiol) are much better at improving lipids than transdermal estradiol.  

Oral vs Transdermal for Lipids:  

The lipid effects of oral estrogens (both CEE and estradiol) on lipids are superior to those of transdermal estradiol.  Multiple RCTs tell us that oral estrogens are superior to transdermal E2 in reducing ApoB, LDL, total cholesterol, Lp(a), and at increasing HDL.  We’re talking a factor of 2-3 times better.   For example, Majoie, 2003 found that oral E2 reduced LDL by 12.6% while transdermal E2 reduced LDL by 4.7%.  They also saw a reduced Lp(a) of 6.6% in the oral E2 group vs no decrease in the transdermal group.  This is one of many RCTs that say the same thing. Oral estrogens (both CEE and Estradiol) are better for improving all lipid markers except triglycerides.  Transdermal estradiol tends to have a more beneficial effect on triglycerides than oral estradiol.  Here are two other studies to review (both RCTs):  Taskinen, 1996, Vehkavaara, 2001, 

More cool science supporting oral estrogen:  

Okay, but are the lipid-lowering effects enough to explain the reduced CHD in women taking oral estrogens?  Or is there more to the story?  

Oral estrogens also behave differently within the blood vessels than transdermal estradiol.  In one study on endothelial function in Circulation, 2000, they took newly menopausal women (average age 55) who were taking either oral estradiol or transdermal estradiol, and they measured their responses to infusions of an endothelium-dependent vasodilator (acetylcholine), which is also found in the human body.  They found that the oral estradiol group reacted to these vasodilators, but the transdermal group did not. In conclusion, they said, “We conclude that oral but not transdermal estradiol induces potentially anti-atherogenic changes in in vivo endothelium-dependent vasodilation and lipid concentrations.”  

We also have evidence that oral estradiol may be slightly better than transdermal at reducing fibrinogen (Zegura, 2003) and homocysteine levels (Smolders, 2005), both known cardiac risk factors. 

The case against oral estrogen:  

If you’re still here (yay!), you may think that I’m pink-washing oral estradiol and making it seem better than it is.  But I want to be fair, so I will address a few of the “hits” against oral estrogen.  Keep in mind that many of the negative associations you and many doctors have with oral estrogen are because of the oral SYNTHETIC estrogens used in most studies.  Yes, these estrogens aren’t great.  They cause problems.  We don’t want them.  But what about oral estradiol?

Blood clot risk (aka venous thromboembolism, VTE, or pulmonary embolism, PE):

Thus far, we have no (as in zero) RCTs that have found an increased risk of blood clots with oral estradiol.  In fact, the studies I mentioned above that used oral estradiol (ELITE, EPAT, DOPS) showed no increase in VTE in the oral estradiol group compared to placebo.  

However, observational studies (Vinogradova, 2019) have found an association between oral estradiol use and blood clots.  And we have other observational studies indicating that, although oral estradiol seems to increase blood clot risk, it is 30% less likely to cause VTE than oral synthetic estrogens (Binkowska, 2022); so, let’s assume that oral estradiol can increase blood clot risk somewhat. I think that’s a fair statement.  But it’s less likely to cause VTE than oral synthetic estrogen.  

What is the blood clot risk in an average population of women taking synthetic estrogen for HRT?  In the WHI, oral CEE increased VTE risk two-fold.  In that study (which included older, more overweight women than most observational studies - both of which are risks for blood clots), they saw 14 blood clots per 10,000 person-years in the placebo group and 34 blood clots per 10,000 person-years in the oral synthetic estrogen group.  So, yes, this is an increased risk, but the ABSOLUTE risk of a blood clot in a woman taking oral estrogen for HRT (especially if she’s young and healthy) is still low.  We give young women oral birth control pills every day, which are known to increase blood clotting risk 3-4 fold.  If CEE increases clotting risk 2-fold and oral estradiol has 30% less risk of clotting than CEE, then you’re looking at a pretty small increased risk of VTE in women taking oral estradiol for HRT.  

Still, I don’t recommend oral estradiol to anyone with a history of blood clots (VTE, PE) or an increased risk of blood clots (ex, clotting disorder, smoker, obese, sedentary).  I also don’t recommend oral estradiol in HRT late-starters (>10 years from menopause onset) because, by that point, we’re unlikely to see many cardiovascular benefits of taking estrogen, which is the primary reason I want women on oral estradiol. 

Elevations in CRP (C-Reactive Protein):   

Some studies have seen increased CRP in women taking oral estrogens.  CRP is considered a marker of increased systemic inflammation. Elevations in CRP are more of a problem with oral synthetic estrogen (CEE), but the risk of increasing CRP seems higher with oral estradiol compared to transdermal estradiol as well.    And this is something worth tracking for all women.  However, whether an elevated CRP caused by oral estrogen is a problem for these women is a question worth asking.  Does an elevated CRP mean that the oral estrogen has caused increased systemic inflammation?  Or is something else going on here? 

In multiple studies on oral CEE, we’ve seen that CRP can go up, BUT we don’t see any other markers of vascular inflammation.  Instead, we see a DECREASE in markers associated with vascular inflammation, such  IL-6, soluble CAM’s, MCP-1, TNFa, s-thrombomodulin, and E-selectin in women taking oral estrogens despite increased CRP (Silvestri, 2003).  From that same Circulation study, the authors noted, “On the one hand, (oral) HRT induces an increase of CRP; on the other hand, it lowers most markers of vascular inflammation, including IL-6, which is the modulator of the liver production of CRP, thereby suggesting that the increase in CRP occurring with HRT is metabolic and not related to an inflammatory response.”

A 2006 review article in Cardiovascular Research (Kwang Kon Koh) similarly concluded: "These observations strongly suggest that increases in CRP following oral HRT may be related to hepatic metabolism rather than a systemic pro-inflammatory response.”  

Finally, it’s worth noting that while the above studies are mostly talking about oral synthetic estrogens (CEE), we have evidence that, while oral estradiol doesn’t always increase CRP (Stork, 2002) when it does increase CRP, that increase is not associated with an increase in other markers of vascular inflammation such as IL-6 and TNFa (Lacut, 2003).

Elevations in Estrone: 

Critics of oral estradiol will say, “What about the fact that oral estradiol increases estrone?”  Well, yes, it can.  But what does that mean?  

Classically, we’ve been taught estrone (E1) is a more “pro-inflammatory” estrogen than estradiol (E2) or estriol (E3).  Estrone is the most common estrogen made after menopause, mainly made by adipose cells. Obese menopausal women have higher serum estrone levels than thinner women.  The more overweight a woman is, the more aromatase activity she has in her adipose tissue and the more estrone she will make.  

Knowing that, let’s discuss what else we know.  Menopausal women (not on HRT) with higher estrone levels have a significantly higher risk of ER+ breast cancer (Miyoshi, 2003), and the risk for estrogen-dependent cancers increases markedly after menopause when estrone becomes the primary serum estrogen (Diaz-Ruano, 2023). Also, high levels of the enzyme that synthesizes estrone from estradiol (17b-HSD1) are associated with worse outcomes in ER+ uterine and ovarian cancers (Diaz-Ruano, 2023).  

Finally, mechanistic studies have indicated that when certain cancer cell lines are exposed to estrone, the estrone “cooperates with TNFa to drive NF-kb activation, inflammation and tumourigenesis,” whereas estradiol does not (Diaz-Ruano, 2023). Another study on ER+ breast cancer cells found that estrone, but not estradiol, “drives invasion and metastasis of ER+ cancer cells in culture” (Qureshi, 2022). 

So, we have evidence in humans that women who are obese (and, thus, have a higher estrone level) are at a higher risk for breast cancer.  However, these studies don’t tell us that estrone is causing the increased cancer risk.  It could just as easily be due to the influence of the highly inflammatory adipose tissue.  Then, we have a few cell culture studies that say estrone may not be as good for existing breast cancer cells as estradiol.

But what do the actual human randomized controlled trials (RCTs) on women taking oral forms of estrogen say?  As mentioned earlier, most studies looking at cardiovascular health used oral estrogens (CEE or E2).  In those studies, they not only saw a reduction in cardiovascular disease if oral estrogen was started early, but they also saw a reduction in breast cancer risk!  In the WHI, they saw a 29% reduction in breast cancer risk in women taking oral CEE without progestins.  In a meta-analysis of all of the RCTs currently available, they found a 23% DECREASE in breast cancer risk in women taking estrogen - and most of these women were on oral estrogen (Chlebowski, 2024).  This is despite the fact that oral estrogen increases estrone.  

Finally, in a weird turn of events, estrone may be HELPFUL in specific populations.  In a long-term prospective study (Antonio de Padua Mansur, 2012), they looked at 251 postmenopausal women aged 50-90, not on HRT, with known coronary artery disease (CAD) or high risk for CAD.  They looked at all their risk factors for CAD, including BMI, and analyzed whether estrone was an independent risk factor for CAD.  They found something surprising:  Serum estrone < 15 pg/ml was an independent risk factor for increased mortality from all causes in these women.  They said, “Higher estrone levels remained an independent variable even after adjustment for body mass index and prevalence of diabetes and dyslipidemia.” and hypothesized that “the better prognosis was due to the possible protective effects of increased physiological levels of estrone.”  Whoa!

Increases in serum SHBG (sex hormone binding globulin):

Finally, a discussion of oral estradiol wouldn’t be complete without a mention of how oral estradiol (but not transdermal) will increase SHBG (serum hormone binding globulin).  SHBG is a very misunderstood transport protein. It’s been villainized when it should be revered.  People think that a high-end SHBG is a negative thing because when you have a higher SHBG, you’ll have a lower free testosterone level.  SHBG (along with albumin) will bind up your testosterone, so you have less of the “active” free form, even if your total testosterone is unchanged.   A low free testosterone can mean you’ll suffer from symptoms of low testosterone (low libido, low energy, depression, etc), so it makes sense that we would want to avoid a higher SHGB level, right?  Wrong. 

A higher (endogenous) SHBG level is beneficial for metabolic health. When I say “higher,” I mean “high-normal,” as in still within the normal reference range for SHBG, which is about 20-120 nmol/L for women.  Higher SHBG levels are associated with more favorable cardiometabolic risk. Observational studies have found that a low SHBG is strongly associated with an increased risk of type 2 diabetes mellitus, independent of sex hormone levels in men and women (Wallace, 2013).  In one study in women with PCOS, they found that the probability of insulin resistance decreases with higher SHBG levels in a linear way such that there’s a 50% probability of IR in women with SHBG of 41 nmol/L, a 33.5% probability of IR at 63 nmol/L, a 25% probability of IR at 76 nmol/L and only a 10% probability of IR at 111 nmol/L  (Biernacka-Bartnik, 2022).  This relationship is so strong that I check an SHBG on every patient, and if it’s low (or low-normal), my first thought is always insulin resistance.  

Although much of the data we have is observational and shows us a correlation or association between SHBG and insulin resistance, we also have some mechanistic data that points to a bidirectional relationship between SHGB and insulin where SHBG may have functions outside of simply acting as a transport protein and may have a role in the pathogenesis of type 2 diabetes mellitus (Wallace, 2013).  

All of this is to say that, yes, oral estradiol increases SHBG.  But, as long as it’s within the “normal” reference range, there’s no reason to believe this is a problem.  Of course, if your SHBG is outside the reference range (either too low or too high), you should be evaluated for other causes of SHBG derangement, such as liver disease, thyroid disease, alcoholism, eating disorders, and obesity).  And, f low testosterone symptoms become a problem when taking oral estradiol (or, frankly, oral birth control pills), I recommend working with a doctor who can prescribe testosterone so that your free testosterone level is brought to the upper half of your lab’s reference range.  

Transdermal vs Oral for Bone, Pelvic Floor, Skin etc:  

While we have little good evidence that transdermal estradiol reduces cardiovascular disease risk or, frankly, breast cancer risk, we do have good data that transdermal estradiol (like oral estradiol) is effective in treating the symptoms of menopause (vasomotor, sexual, musculoskeletal, cognitive, etc) and for improving bone health, vaginal/pelvic floor health, skin health as well as several markers of metabolic health.  

Both transdermal and oral estradiol have beneficial effects on blood glucose and insulin sensitivity.  In one study with transdermal estradiol, they saw twice as many cases of diabetes in non-users vs users.  Both transdermal and oral estradiol can also improve blood pressure and body fat distribution (reducing the highly inflammatory visceral fat).  

Transdermal estradiol is better at reducing triglycerides than oral estradiol.  

Estrogen and cognitive health:  

We have limited data on the possible neurocognitive benefits of bioidentical transdermal vs oral estradiol as studies have yet to compare these two directly (and few even used bioidentical hormones).  Here’s what we do have… 

WHIMS (JAMA, 2003 - part of the WHI dataset), found a 49-76% increased risk of dementia in older women (>65 when starting HRT) taking synthetic hormones (CEE + MPA).  We know that oral CEE increases matrix metalloproteinase (MMP) much more than oral or transdermal estradiol and that MMP will break up atherosclerotic plaque, potentially leading to heart attacks, strokes, and TIA’s (transient ischemic attacks) that can lead to vascular dementia.  This is likely why we saw an increased risk of dementia in this study.  

The KEEPS Cog study found that women receiving transdermal estradiol performed better on cognitive tests than those receiving oral synthetic estrogen (CEE).  

In an RCT looking at HRT for verbal recall (Tierney, 2009) they gave women oral estradiol (1 mg) with progestin. They found that women with average or above average initial scores on delayed verbal recall tests who took HRT had less decline in short-delay verbal recall at 1 year and 2 years.  Women who started with lower verbal recall tests did not benefit from HRT. 

The EPAD cohort study (Saleh, 2023) found that HRT use reduced cognitive decline and helped prevent the shrinking of the amygdala of the brain, but only in ApoE4 gene carriers.  Multiple types of estrogens and progestins were included, but differences between types of estrogen weren’t discussed. 

In the Rasgon study (Rasgon, 2014) they recruited 50-65-year-old women and randomized them to either oral CEE, transdermal E2 (0.1mg) or placebo for two years.  They found that women taking transdermal estradiol had fewer negative metabolic brain changes than women taking CEE or no HRT.  Interestingly, women taking synthetic progestin with their estrogen exhibited negative brain changes, similar to the no-HRT group (another reason I never give synthetic progestins - they knock out many of estrogen’s positive effects).  

In a 2021 meta-analysis by Zhou (Zhou, 2021), only two of 23 studies were done on women <60 years old when starting HRT, and the overall results were that HRT did not improve cognition. In the two studies in younger women, one showed no effect on cognition and one showed that CEE + MPA improved cognition. None used bioidentical estradiol.  

The Wrap-Up:  

In summary, if all of the stars have aligned and I have a low-risk-for-blood-clot woman who is within 10 years of menopause onset and who understands that there may be a small increased risk of clot with oral estradiol compared to transdermal, I will preferentially use oral estradiol.  Oral estradiol has stronger evidence for reducing cardiovascular disease risks and improving lipids than transdermal estradiol.  

Suppose I have a woman who is either >10 years from menopause onset or high risk for blood clots. In that case, I will instead offer her transdermal estradiol, which I know is the safest form of estrogen and which, like its oral friend, will reduce her menopause symptoms and will reduce her risk for osteoporosis, UTIs, urinary incontinence, vaginal dryness/pain, metabolic syndrome, visceral adiposity, and skin aging.

I will never prescribe the synthetic version of estrogen, Premarin (CEE), and I will always only use the bioidentical form of progestogen (oral natural progesterone) and not its evil twin (synthetic progestin).  

I will always start estradiol as soon as possible - either in late perimenopause or in early menopause.  

Finally, I will add testosterone therapy if she’s symptomatic and has low serum-free testosterone.  

Hopefully, we’ll see more and more research dollars poured into looking at oral and transdermal bioidentical estradiol in the coming years.  If I see more evidence that transdermal estradiol is effective in cardiovascular disease prevention, I’ll be happy to reevaluate my approach.  But, for now, I have to follow the evidence and go where it leads me…. To the Isle of Misunderstood Hormones and Well-Founded Oral Estradiol Fetishes.  

Post Script:  I started learning about bioidentical hormone replacement therapy (BHRT) in 2012. Before that, I’d been an emergency physician who had never even heard of estradiol, much less other forms of estrogen.  The first few years I treated hormone patients, I followed the teachings of several functional/integrative medical groups - all of whom recommended transdermal estradiol.  It wasn’t until 2016 that I attended my first lecture series by Dr Neal Rouzier, a world-renowned expert in bioidentical hormone replacement therapy.  Dr Rouzier is a staunch supporter of oral estradiol for cardiovascular disease prevention.  

Despite what I’d learned from Dr Rouzier, I was still nervous about giving oral estradiol because almost every other menopause organization taught that transdermal was the way to go.  NAMS (now called the Menopause Society) recommends transdermal. 

To wrap my head around the risks and benefits of oral vs transdermal, I did my own research, creating detailed spreadsheets and going through all relevant studies myself. I didn’t rely on summary statements or meta-analyses.  I went to the primary research.  This article results from that research, which has taken me almost a year.  I am incredibly grateful to Dr Rouzier and the physician group he created (Worldlink Medical). I consider them some of the best, non-biased sources of information about bioidentical hormone replacement worldwide.