Estradiol - Supplementation, Perimenopause, Safety, and Beyond - A Total Review
We need AI.
There is so much conflicting information on hormones and estradiol specifically that you start to wonder if there's a grand conspiracy.
England is literally running out of HRT (hormone replacement therapy) and suddenly a study comes out on safety.
You dig into that study and the difference was between 6 and 8 women. So 2 women had increased risk. Out of thousands!
And... it was with synthetic hormones (we'll get into that below).
Don't get us started on the delivery method: patch, gel, or pill.
So... we're going to do what we had to with progesterone and CBD... a deep dive into all the real questions that women are asking around the time of perimenopause like I did.
And still do!
My story is here but perimenopause sent me reeling into 24/7 panic attacks, anxiety, and all the medications thrown at me (benzos, SSRIs, BP drugs, heart meds, etc) almost killed me.
In the end, bioidentical hormones were 95% of the fix (with some help from CBD and nutrient support) so let's get to the lingering questions.
When you're coming out of your skin already (see perimenopause anxiety), and reading all the scary stuff online, it can send you into a tailspin.
There's fascinating new research on how the endocannabinoid system and CBD may help protect from hormonal-driven cancer.
We're going to hit the research.
Real research and dig deep into the pathways of our star estrogen player, estradiol.
Don't worry, we'll explain what it is, how it works, and why it's so critical to every working system in your body.
We'll cover these areas:
- What is estradiol (are estrogen and estradiol the same??)
- The relationship between estradiol, estrone, and estriol
- What is the difference between estrogen and estradiol
- What happens to estradiol during perimenopause
- What does estradiol do the body and brain
- Symptoms of estradiol dropping
- What are levels of estradiol as we age
- Is it safe to take estradiol
- Bioidentical estradiol versus synthetic
- What's the best way to take estradiol
- Do you need progesterone with estradiol
- The endocannabinoid system and estradiol
- CBD and estradiol - an insurance policy
- Estradiol and alcohol
- Estradiol and weight gain
- Estradiol and cholesterol
Goodness...lots to cover and some of those topics are going to be marathons.
We were just so tired of the lack of coverage based on research so let's get into it.
First up, an introduction to your most powerful sex and steroidal hormone, ladies.
What is estradiol?
Are estrogen and estradiol the same?
Estradiol is the workhorse "flavor" of estrogen.
There are actually three different chemicals that are part of the estrogen family. Estradiol is referred to as E2.
Of the three, estradiol is the critical lever in the body and brain (outside of pregnancy).
Technically, estradiol is a steroid hormone (one of about 50) which ultimately comes from the mother of all these hormones, pregnenolone (check out the full review here - fascinating).
Ultimately, estradiol and all the sex hormones are made from cholesterol.
Yes, the boogey man of the media. In fact, it's the so-called "bad cholesterol" that is the building block for pregnenolone which eventually gets converted downstream to estradiol.
Check out new research on how the fat being deposited in arteries actually has the signature of bacteria...mouth bacteria.
Not liver or mammal signatures.
Then again, statins are a billion-dollar business.
We may be depleting our raw material for sex hormones by going after cholesterol. We digress.
Estradiol can also be made from fat cells... is the body trying to make up for lost estradiol by increasing fat content?
Estradiol is primarily made in the ovaries/testicles but resulting production (though minor) shifts to the adrenals after menopause.
Interestingly, men need estradiol as well and it actually helps to shape their bodies.
Estradiol is critical for puberty and reproduction but we want to look at its many other effects in the body and brain... especially as levels drop during perimenopause.
In fact, there's too much focus on estradiol (or sex hormones in general) for reproduction as we have estrogen receptors on every cell in our body.
We'll occasionally use estrogen and estradiol interchangeably since estradiol is leading that pack.
Let's now look at the difference between the three estrogens since this plays into the supplementation question.
The relationship between estradiol, estrone, and estriol
You have three different versions of estrogen:
- Estrone (E1)
- Estradiol (E2)
- Estriol (E3)
Let's look at each of these first.
Estrone (E1) functions more as a precursor for estradiol.
The pathway is actually:
Cholesterol -> Pregnenolone -> Androstenedione -> Estrone -> Estradiol
Estrone is a much weaker version of estradiol.
Yes, it can interact with the estrogen receptors (there are two of them A and B) but at much lower levels:
In accordance, the estrogenic activity of estrone has been reported to be approximately 4% of that of estradiol
We can think of estrone (in its sulfate form) as a reserve for estradiol.
Estrone is relevant to health and disease states because of its conversion to estrone sulfate, a long-lived derivative. Estrone sulfate acts as a reservoir that can be converted as needed to the more active estradiol. It is the predominant estrogen in postmenopausal women
Really, there are two major differences between the three estrogens:
- Level of action on the estrogen receptors
- Which receptors they are bound to
In terms of level, there's a clear hierarchy:
The estrogenic potency of 17β-estradiol is known to be 12-fold greater than that of estrone and 80-fold greater than that of estriol, making the total estrogenic efficiency of 17β-estradiol much greater than that of the other two combined.
Estriol is a very weak estrogen that spikes during pregnancy. Up to 1000 times!
Otherwise, it's generally at very low levels in the blood and gets broken down quickly.
Think of it as a turbo-boost for pregnancy-related changes.
It's very common to include it in estradiol supplementation as a protective element which we'll investigate below.
The main estrogen receptors affected (ER-alpha or ER-beta) are a little more interesting.
The different receptors are found throughout the body but with differing concentrations.
One important difference in safety:
The beta subtype seems to have a more profound effect on the central nervous and immune systems, and it generally counteracts the ERα-promoted cell hyperproliferation in tissues such as breast and uterus
- the A receptor is tied to the "Growth" effects of estrogen (both good and bad)
- The B receptor deals more with housekeeping effects (mood, sleep, heart, etc)
By looking at so-called, "knock out" mice, scientists are showing very different effects from knocking out either receptors.
They truly have different roles and that's very important to our discussion between the three versions of estrogen.
There is emerging research of ERa being more "pro-growth" and proliferative and ERb opposing this effect across many different pathways.
For example, in cancer:
In many breast cancers, ERα activation by estrogens is generally considered responsible for the enhanced proliferation, whereas this is counteracted by the presence of ERβ, which exerts an antiproliferative effect
Look, cancer is the primary fear woman have for hormone replacement starting with a study in the early 2000s that scared the bejesus out of millions of women.
Who consequently stopped hormone replacement.
We'll look at new research there and ways to protect from this effect below.
Let's clear up a quick point of confusion.
What is the difference between estrogen and estradiol
Estrogen is a general term for hormones that can bind with and affect the Estrogen receptors.
Estradiol is the most potent form of estrogen so they're used interchangeably.
Keep in mind that all three activate the estrogen receptors, just in different levels across the two receptors.
The real point to our conversation is what happens when levels drop during the monthly cycle and of course...at perimenopause!
Estradiol versus Estriol versus Estrone? Does it matter?
There's a great deal of confusion and different information on ratios of estrogens for supplementation.
Is estriol protective? Hence the bi-est formula (containing 20% estradiol and 80% estriol).
What about estrone... is that any different?
First, here's a general guide to "natural" levels but keep in mind that estrogens can swing wildly:
The physiological proportion of E1, E2, and E3 in human blood is about 33% E1, 45% E2, 10% E3, and about 10% metabolites of E1 and E2
They are all different strengths of "estrogen" but which receptors they interact may figure into this calculation.
With estradiol as the standard, binding affinity for both estrogen receptor (ER)-α and -ß is equal at 100. Estrone has a binding affinity for ER-α of 60 and for ER-ß of 37. Estriol binds to ER-α with an affinity of 14 and to ERß with an affinity of 21. Therefore, estradiol has the strongest binding affinity for both ER-α and -ß.
Affinity just means how strongly it's drawn to that particular receptor.
So these ratios are actually providing some clues.
Aside from weakness of interaction, estriol appears to have a higher liking (21 versus 14) for ERb while estradiol is equal (and more powerful) and estrone is quite a bit more ERa-centric.
Research is pointing to ERa receptor activity (and genes) being more tied to trophic or growth elements than ERb which is the cancer link.
Keep in mind, you can view the excessive loss of estradiol during perimenopause as being the opposite of growth or atrophy.
One small example in the brain:
The action of estrogens may occur via the increase in the levels of neurotransmitters, which may enhance neuronal growth and formation of synapses
Why is estriol touted as protective?
Welcome to the ever-changing research on hormones!
There was also an original line of study that pointed to a specific receptor called GPER that might be tied to certain cancers as a result of estradiol specifically.
Estradiol is the only flavor of estrogen that works with GPER.
These so-called, triple-negative breast cancers (because they don't interact with ERa, ERb, or HERs receptors) appeared to be blocked by estriol.
That was 2014.
Newer studies are showing that GPER activation is actually tumor-suppressive!:
low protein expression of GPER is not only significantly associated with clinicopathological and molecular features of aggressive behavior but also significantly associated with adverse survival of breast cancer patients.
Other research even pointed to the so-called triple-negative breast cancers:
GPER functions as a tumor suppressor in triple-negative breast cancer cells
Goodness...the swings are enough to give you whiplash on hormone research.
So... we need AI!
Interestingly, when you get rid of GPER activity, you get lots of bad results:
Female GPER knockout mice display hyperglycemia and impaired glucose tolerance, reduced body growth, and increased blood pressure
Only estradiol activates it...hence the spike of diabetes and blood pressure for women after menopause.
Did we mention that hormones are important to every facet of your health?
We'll see later how certain substances that bind with ERb exclusively appear to convey protection from any downside of hormonal expression.
Our goal (my goal really as a 49-year-old walloped by perimenopause who was SAVED by hormone replacement) is simple.
Find out what works. Find out what's safest. Add any protections along the way to make the profile better.
To that goal, put a checkmark by ERb receptors being the desired goal.
What happens to estradiol during perimenopause
As does progesterone.
Unfortunately, it may not be a gentle, slow approach to touchdown (menopause).
Here's a good description of what I had:
Thus, as a woman ages, there is not a progressive downward spiral in the estrogenic milieu, but instead a "roller-coaster" in estrogen production
There can even be spikes of estrogen as the body's trying to serve dinner on a wobbly table.
The ovaries can have spurts of hormonal activity and you'll definitely feel them.
This speaks to feeling fine one day (even with hormone replacement) and suddenly getting thrown for a loop.
There's a great review of this process (if we can call it that) here:
Drops in progesterone and estradiol are the two big changes in perimenopause that set off a cascade of other effects.
Estrogen levels drop from a peak of 210 (average) in our 30's to about half that by perimenopause.
It then starts to drop significantly.
There's a good graph of it here:
In fact, it drops right off the map:
During the first year of menopause, women lose on average 80% per year of their estrogens
On a side note, run a search for "hormone levels by age".
You're going to see a full page on testosterone.
Who says our society discounts women after reproduction!
Testosterone drops in women as well but that's a separate article (with its own effects).
Back to estradiol.
Just look at the ranges for a typical hormone test:
- In premenopausal females, normal estradiol levels are 30 to 400 pg/ml.
- In postmenopausal females, normal estradiol levels are 0 to 30 pg/ml.
Interestingly, estrogen levels start to drop late 30's and even early 40's.
In a perfect world, our OBGyn's would test hormones early in life to establish a baseline.
God forbid, maybe as part of our annual exam.
We can then spot irregular levels and changes over time.
I wouldn't have been hit so hard at age 47!
The estrogen drops to almost nothing by the time perimenopause is done as adrenals and other areas try to compensate for the drop by ovaries.
This is the whole bogus (in our opinion) "Adrenal Fatigue" that even the naturopaths have bought into with weird pig hormone pills.
Those are not going to feel great if you have histamine issues due to dropping progesterone!
Fat is also a good source of estrogen (which we'll get into below).
Why is there a mad dash by the body to compensate for estradiol if it's only for reproduction like most websites (and doctors) seem to think?
Get ready to be amazed by your "sex hormone".
What does estradiol do the body and brain
Let's start by looking at where the different receptors are. This can help.
The ERα is found in endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus. In males, ERα protein is found in the epithelium of the efferent ducts.
The expression of the ERβ protein has been documented in ovarian granulosa cells, kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells.
ERalpha appears to be more "reproductive" in nature.
The ERbeta receptor? Pretty much everything else.
"Brain" is a pretty big umbrella.
In fact, we challenge you to pick a part of the body and NOT find a direct relationship with estrogen.
For example, new research shows that estradiol directly interacts with the endocannabinoid system (our favorite subject) which is tasked with balancing:
- The nervous system (neurotransmitters)
- The endocrine system (hormones!)
- The immune system (hello autoimmune disease)
Generally speaking (and leaving lots out), we see big impacts from estradiol loss here:
- Brain and nervous system function (mood)
- Cardiovascular health (heart)
- Bone health
- Weight and energy
Just one (of thousands) of examples on the last point:
Others had traced the effects of estrogen on energy balance specifically to estrogen receptor-α (ERα). When her team deleted those receptors from the entire brains of mice, "we got very, very fat mice,"
Without eating more calories!
We'll look at that in more detail below but the point is this.
Your body has been use to a certain level of estrogen for decades now and it's suddenly dropping.
Think of a river with lots of streams and offshoots going to every cell in the body.
Yes, ligaments and tendons have estrogen receptors (see joint pain below).
That river starts to dry up with the streams going first.
To give an example, we're going all the way down to a basic "currency" in the cell.
Just to zoom into a tiny piece of the puzzle, a certain chemical state is a known biomarker of aging in the brain.
Estradiol reverses it:
Estradiol Reverses a Calcium-Related Biomarker of Brain Aging in Female Rats
One of a million examples in the body and brain.
Look, this experiment looks at calcium channels in the brain. You can't get to a more basic building block (calcium increases and decreases basically control the activity of a neuron or cell).
estrogen (17β-estradiol, E2) affects calcium-dependent activities associated with cognition.
Cognition. A fancy way to say thinking.
We could go and on but we need to find out how to replace estradiol and the safest approach.
Just know that your younger body functions well partially because of estradiol.
Just a quick look at the common symptoms from estradiol dropping.
Symptoms of estradiol dropping
You'll find this at many sites so we'll just touch on it.
Interestingly, many of the symptoms of dropping estradiol can mimic what happens during PMS.
We have an issue with the usual list of symptoms from estradiol levels dropping:
- painful sex due to a lack of vaginal lubrication
- an increase in urinary tract infections (UTIs) due to a thinning of the urethra
- irregular or absent periods
- mood swings
- hot flashes
- breast tenderness
- headaches or accentuation of pre-existing migraines
- trouble concentrating
Those are the tried and true listed symptoms from most sites.
That's a very narrow view in light of new research and the sheer breadth of what estradiol does.
It also doesn't speak to what we've heard from other women in perimenopause.
Here's a list of what I dealt with:
- A machine feeling like I was sitting on top of a washing machine
- Racing heart at night
- Hyper awareness of my heart
- brain fog with tunnel vision
- hyper sense of smells
- increase allergies
- digestive problems
- increase in gas and heartburn
- heavy periods two times a month
- Small ovarian cysts
- Thinning hair
- night sweats
- Social anxiety
- Sweating and vibration legs
- Joint pain and spotted pain all over the body
- Rolling panic attacks 24/7
- Resulting insomnia
Some of this is progesterone as well.
There are obviously other players at work here (genetics, stress levels, weight, lifestyle choices, etc) but many women are finding that drops in estradiol mean literally feeling like you're in a different body (one you don't like very much).
So when that doctor tells you that your levels are normal and writes a script for Lexapro, go get a Dutch test (or equivalent) to see where your levels are.
Don't suffer. My story is here.
When you do look at that Dutch test, what can we expect for levels?
What are levels of estradiol as we age
Speaking of the Dutch test, check out their report here:
On page 2, they list the three E's.
E2 (estradiol) is shown with a normal range of 1.8 (ng/mg) to 4.5 in the luteal phase. That's when estrogen drops during the regular cycle.
What about menopause levels?
.3 to .9.
So from a low of 1.8 to .3 of a chemical that every cell in our body and brain has receptors for.
That's for a sample 40 year woman so levels have already dropped a bit (just starting really).
That being said, the age of perimenopause start is getting earlier all the time.
Just check out the Reddit perimenopause board where women are entering it in their early 40's (and even late 30's).
That's a whole other question as it matches the early puberty starts as well.
So...if estradiol is safe, let's get started!
Of course, it's more complicated than that.
We have to wade through conflicting studies across the last few decades.
Let's get to the real question for this entire article.
Is it safe to take estradiol
First, a quick history lesson.
When researchers started to see the studies on estradiol and hormone replacement for women's health (body and brain), the birth of hormone replacement began.
Originally, the estrogen was derived from horses (so-called equine estrogen) and synthetics.
Premarin (back in 1942) was the blockbuster drug that resulted and boomed until the 70's when a link with endometrial cancer was found.
They added progestin (synthetic progesterone) to offset the risk and make it "safer" (or so they thought).
By 1992, it was the biggest selling drug on the market! (so I guess, the symptoms aren't just in our head).
Then, the WHI study came out. 2002
All hell broke loose.
Almost overnight, some 80 percent of American women who had been using hormones stopped cold turkey.
Funny how the warning for long term use in that review was issued by a pediatrician. A male pediatrician.
Here's the rub.
Follow up studies found a curious wrinkle.
Women who started hormone replacement 10 years into their menopause (late starters) had the risk.
Women who started earlier did not.
In fact, the basic takeaway was this...the women who started late were reflecting the results of reduced hormones for that 10-year gap.
Meaning...estrogen and progesterone are incredibly important across the body and brain.
Their updated review results:
Among postmenopausal women who participated in 2 parallel randomized trials of estrogen plus progestin and estrogen alone, all-cause mortality rates for the overall cohort in the pooled trials were not significantly different for the hormone therapy groups vs the placebo groups (27.1% vs 27.6%; hazard ratio, 0.99 [95% CI, 0.94-1.03])
This means that women getting estrogen by itself or estrogen plus synthetic progesterone had very similar risks of dying from all causes.
In case you're wondering...the hormone group fared better than placebo there (27.1 versus 27.6)!
Interestingly, what researchers did find as a result is that women who stopped hormones due to the WHI report had a higher incidence of hip fractures.
Another study, from Yale, extrapolates that more than 91,000 women ages 50 to 59 who had hysterectomies and were not prescribed estrogen died prematurely from cardiovascular disease between 2002 and 2012.
There's a fascinating review of just how botched that initial report was:
Later analysis of WHI data showed these younger women had an absolute risk of 12 adverse events per 10 000 women — less than a third of the risk of adverse events noted among women aged 70 to 79 — as well as fewer cancers, fractures and deaths from any cause compared to the placebo group.
A pretty good description of the real risk is here:
For example, in 50-60-year-old women taking combination estrogen-progestin therapy, the estimated additional risk of breast cancer is 3 cases per 1000 women on five years of therapy. That is a very small absolute risk. Further, in those 50-60-year-old women taking estrogen alone, it is estimated that there will be 2.5 fewer cases of breast cancer per 1000 women on treatment for five years.
So starting earlier appears to be beneficial and that's without the protections of progesterone and bioidenticals.
Some of the same warnings for stroke, cancer, and blood clots are on the products still (products which are completely different from those studied in the WHI study)
Why are there so many conflicting reports on estradiol safety when the boogeyman of the field (that WHI report) was reversed?
Keep in mind that the study involved synthetic horse estrogen (we'll get into that below).
The general message now appears to be HRT is for short term duration of 5-7 years and should not be for general wellness and prevention.
Of course, this is written by male doctors primarily.
Let's dig deeper into other issues to be resolved.
The two big questions out there in the internet ether and medical arena are breast cancer risk and thrombosis (blood clots).
We have combed through the studies and it's very confusing.
First, the bulk of research is on synthetic estrogen because that matches the bulk of what's sold on the market.
To see the difference, look at this NIH comparison for progesterone versus progestins:
Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55–0.81.
That's a huge drop in risk..33% less than synthetics.
That's only one aspect of this debate and we'll get into next.
As for cancer and thrombosis question, we'll cover those specifically below.
Then there's the conflicting information on estradiol metabolites.
The 2, 4, and 16 alpha-hydroxyestrone
On one hand, some research has tied 16 to being "bad" and 2 and 4 to being protective. here
Other research isn't this bearing this out. here
You can see the breakout on the Dutch test but we want more research.
This feels a little early as the body's a complicated thing and we'd rather focus on actual outcomes of supplementation and risk.
So for right now, the question appears to be on long term hormone replacement safety.
One note...you really have to set your search to "recent year" with this as there is so much old and outdated information.
Everyone appears to have an agenda as well.
We want to get to the bottom of it based on real research.
Speaking of research, we have to parse out a great deal of it because of the next topic.
Bioidentical estradiol versus synthetic
Have we not learned this lesson YET?
Synthetic fat - hydrogenated oil has probably wiped out a generation:
Research has proved the direct connection of trans fatty acids with cardiovascular diseases, breast cancer, shortening of pregnancy period, risks of preeclampsia, disorders of nervous system and vision in infants, colon cancer, diabetes, obesity and allergy
Did you catch the female bent of those symptoms?
This is further evidence that consumption of artificial sweeteners adversely affects gut microbial activity which can cause a wide range of health issues.
The gut bacteria (microbiome) is the new revolution in health (and intimately tied to estradiol levels as well).
See CBD and probiotics for anxiety as an example.
In fact, in our 1000's of hours of research for CBD, when synthetic cannabinoids are used (such as Epeliodex - a synthetic analog to CBD), the side effect profile is much worse than just CBD.
Night and day.
Look...synthetic versions allow companies to patent what is a naturally occurring substance.
The new post-partum depression med sells for $25K and is a synthetic version of allopregnanolone.
You can buy its precursor (pregnenolone) here for around $10.
What about synthetic hormones?
First, bio-identical estrogen is typically extracted from Mexican yams or soy, two natural sources of estrogen.
What about safety.
We saw the NIH comparison.
A really good introduction is this comparison between bioidentical progesterone and progestins:
- beneficial for cardiovascular health
- stimulates hair growth
- has anti-androgen properties
- generally good for mood and sleep
- helps to prevent breast cancer.
- increases the risk of blood clots
- can cause hair loss
- can be androgenic, or “testosterone-like”
- may cause anxiety and depression
- increases the risk of breast cancer.
Love her stuff by the way...very concise and well researched.
That's progesterone...what about estradiol?
It's really hard to get a clear view.
Researchers throw around estrogen but mean equine (from horses), synthetic, and bio-identical estradiol (or estriol or estrone or a host of different estrogen metabolites).
One study reviewed efficacy and risk for synthetic versus bioidentical progesterone and estriol:
physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal-derived counterparts.
Another study looked at estrogen in conjunctions with either synthetic progesterone or bio-identical:
Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55–0.81.
That's a big difference...33% reduction!
Still, that's more progesterone.
Then there's TX-001HR.
It's an FDA approved bioidentical progesterone and estradiol combination.
Their results after 12 months (we need longer periods of course):
No endometrial hyperplasia or cancer was found with any of the doses.23
Hyperplasia is a thickening of endometrium wall that reflects proliferation from estrogen.
Remember, estrogen is a hormone for building things!
Estrogen promotes endometrial epithelial cell growth, while progesterone inhibits estrogen-mediated epithelial cell growth in the endometrium (Clarke 1990; Carlson 2012).
Remember how the current question du jour is long term use.
In a major analysis of that original report, when synthetic progestin was used with estrogen, there was an increase in breast cancer risk.
However, the effect for estrogen (without the progestin):
Estrogen-alone decreased breast cancer risk, an effect that became statistically significant over the total follow-up time of 13 years.
We want to see longer durations and head to head comparisons of bioidentical estradiol, synthetics, and placebo.
It's just 47 million women worldwide entering menopause each year. That's all.
No fair looking after us after we give birth and raise the next generation.
Work with your doctor and make the best decision for you.
Personally, bio-identical is the only course for me as my body doesn't seem to like anything synthetic (thanks histamine).
Keep in mind that you can get FDA-approved bioidentical estradiol.
In fact, most of the estradiol on the market comes from Mexican yams or soy but the levels may be more controlled.
On a side note, a great deal of the scary reports and side effects are the result of equine or horse derived hormones like Premarin, the original hormone replacement from last century.
That's not even a question.
In a large study comparing equine derived estrogen to estradiol, incidents of heart problems and vein thrombosis were significantly lower with estradiol:
The odds ratio (OR) for venous thrombosis was 2.08 for women using CEE, compared with women using estradiol (95% confidence interval [CI], 1.02–4.27; P = .045). The OR for MI was 1.87 for women using CEE, compared with women using estradiol (95% CI, 0.91–3.84; P = .09).
Let's look at the next big source of confusion.
What's the best way to take estradiol
Here's the other big question that comes up one a woman decides to look at hormones.
Gel, pill, or patch.
Again, research is all over the place.
There's a push towards patch or gel with a safety bent for estradiol.
The thought is that when estradiol goes through the liver, it produces metabolites that contribute to health issues.
This is based on the following:
Non-oral administration of estrogen offers advantages due to the lack of first-pass hepatic metabolism, which in turn avoids the increased hepatic synthesis of clotting proteins, C-reactive protein, triglycerides, and sex hormone-binding globulin.
Let's look at each of these (someone has to).
First, thrombosis or blood clots.
It's probably the biggest determinant between skin versus oral.
First, we have to separate out the horse-derived and synthetic hormones out.
The difference is well-established for both from straight estradiol (bioidentical).
Secondly, we have to parse out the studies where they use synthetic progesterone alongside the estrogen.
See how this can get so muddied?
First, we'll start in the mud.
Some good research using synthetics can be found here for both hormone contraception (HC) and hormone replacement (PHT) with VTE being Vein Thrombosis Event (blood clot):
Although transdermal PHT is reported to be safer with respect to VTE, transdermal HC is reported to increase the risk of VTE at 4 to 8 per 10,000 women compared with 2 to 5 per 10,000 women using oral HC.
In the landmark Leiden Thrombophilia Study, the absolute risk for VTE was estimated at 0.8 per 10,000 per year among nonusers and 3.0 per 10,000 per year among HC users.
There may be ways to offset this risk (more on that below).
There were many other factors at work here including a mutation you can check for (basically, a family history of thrombosis or blood clots).
That absolute risk is pretty ridiculously low and we're talking synthetics.
We saw above the comparison between horse estrogen and estradiol.
Just a head's up...the first results were for birth control so if you've used birth control before, that's the same process (albeit, not synthetic with estradiol).
At least now we can see the result of transdermal (skin) versus oral.
.0006 versus .0003.
The risk for thrombosis is generally in the 1st year of use.
We would love to see this same study but with bio-identical if the issues with synthetic progesterone are any indication.
Again, one more reason for bio-identical estradiol:
Study of long Duration Oestrogen after Menopause (WISDOM) trial,8 showed a marked increase in the risk of VTE in women using oral non-bioidentical HRT.
Next up...C-reactive protein, triglycerides, and cardiovascular.
C-reactive protein is a measure of inflammation.
New research on that:
After controlling for age, menopausal age, body mass index, and basal CRP, no significant change in CRP was observed in the oral estrogen group
That's a 2019 study...see how fluid this whole field is?
Triglycerides and cholesterol.
There were original reports on triglycerides and cholesterol increasing from hormone replacement.
Again, we have to parse out horse derived and synthetics.
What about straight estradiol effect?:
A reduction in plasma triglyceride concentrations was observed in postmenopausal women after estradiol treatment but not progesterone or testosterone, according to research in The Journal of Clinical Endocrinology & Metabolism,
In fact, an interesting study we referenced in our review of pregnenolone showed that hormone replacement dropped cholesterol.
Think about that...dropping cholesterol simply by boosting hormones after perimenopause.
It's fascinating but basically the body is trying to make up for lost estrogen by boosting its raw material, cholesterol!
Check out that review at the link above.
Preg may be a great way to get progesterone back.
The astounding result from this study was that by properly replacing the steroidal hormones lost to normal aging, 100% of the subjects experienced a significant reduction in blood cholesterol levels.
The net takeaway...if transdermal works for your lifestyle, that's fine.
Research (even with synthetics) found no difference in risk for blood clots with skin and very small differences with oral.
I swim every day and use the jacuzzi which might make the patch difficult (there are pretty good boards discussing the different options).
We really need a bioidentical comparison of the different deliveries to compare apples and apples.
In terms of bio-availability or how much estradiol actually gets into the bloodstream, we have some data there.
You can find a good review of bioavailability here:
Oral estradiol (if micronized which most are) appears to have a great bioavailability and less variability within a given person (not between due to different liver function):
The doses used of the transdermal gel and the patch roughly correspond to each other with regard to the amount of oestradiol absorbed whereas the bioavailability from the tablet was significantly higher than from the gel.
The patch was more stable in delivery where the gels fluctuated more. The pill varied according to liver function but was faster acting.
Again, much of this research is synthetic which hopefully we've shown processes differently in the body.
Hopefully, the research catches up since 1/3rd of women taking hormone replacement use bioidenticals.
If we were betting folks, we would wager on a better profile for bioidentical estradiol.
Do you need progesterone with estradiol
Progesterone is the other hormone that drops significantly during perimenopause.
In fact, it drops first and practitioners in the know generally will supplement it first before estradiol.
You can still have periods towards the end but make no progesterone.
Basically, ovulation didn't occur and so progesterone was not made.
More on that process here.
First, we definitely want bioidentical progesterone and not synthetic progestins.
There's quite a bit of research on the different outcomes between the two in case you run into a doctor who calls bioidentical snake-oil.
Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55–0.81.
That's just one aspect albeit, an important one.
It also speaks to the original risk brought up by the WTI study which scared everyone to pieces as they used synthetic progestins!
Same goes for cardiovascular, blood sugar-insulin issues, and blood clots.
Generally speaking, estradiol is a growth factor while progesterone is a calming factor.
It's very similar to glutamate and GABA in the brain.
As for the endometrial hyperplasia (basically, too much growth of the lining which can foretell cancer):
Importantly, P4 used in HT prevents endometrial hyperplasia from estrogens while helping relieve vasomotor symptoms and improving quality-of-life measures.
P4 is progesterone (bioidentical).
Another study looked at progesterone (bioidentical versus synthetic) for estrogen's positive effect on exercise after stroke:
Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women.
In fact, when bioidentical estradiol was combined with progesterone, a study found positive effects on all the biomarkers we've discussed above (plus many more):
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.
We could almost stop there.
- Blood sugar
- Inflammation (c-reactive protein)
- Blood clots
- Anxiety and Depression
- General menopause symptoms
- Pain thresholds
After 3 years...all better.
Now, this is transdermal (via skin).
Progesterone has a separate article here but it's clear from the research that there is a buffering or protective element (aside from its own benefits in the body and brain) with estradiol.
Next up...estradiol's intersection with our wheelhouse.
The endocannabinoid system and estradiol
At IndigoNaturals, we focus on CBD and the endocannabinoid system.
Why on earth did we put all this time into estradiol?
First, we stumbled on estradiol via a crushing perimenopause (story here).
We're talking earth-shattering perimenopause...not hot flashes (but we had those too).
It was so frustrating researching the hormone side of things even though it was saving my life!
This review of the research was as much for me personally as it is for our viewers.
There's so much bad and old information out there (and in on box warnings) that we needed clarity.
Let's look at the endocannabinoid system.
Remember that this system is tasked with balancing other key systems.
- Nervous system - neurotransmitters such as serotonin, dopamine, GABA, etc
- Immune system - inflammatory and stress response
- Endocrine system - Hormones!!!!
To simplify it, this system sits above the other ones and adjusts to "stress" on different components.
Perimenopause might be the biggest stressor your body ever sees!
These hormones are marbleized into every system of your body.
And they're plummeting!
The "camel's back" IS the endocannabinoid system from this stress.
First, to the cancer scare of hormone replacement.
The endocannabinoid system directly governs cell birth and death.
CB1 and/or CB2 receptors are coupled to several signaling pathways directly involved in cell survival, proliferation, and apoptosis, including p38 MAPK, cyclic AMP, PI3K-Akt, RhoA, JNK, EGFR, ERK,24 and ceramide pathways.1,19,25–30
This results in an anti-cancer effect for specific cannabinoids (we'll look at CBD below):
A variety of mechanisms are likely to contribute to the anticancer effect of CB ligands.
CB just means cannabinoids and we have two receptors CB1 and CB2.
Of course, the relationship between estradiol and this system is extensive.
If you want to see how powerful estradiol is in the body, look no further than anxiety and depression.
Stay with us...we'll walk you through it. This is too important (and exciting!).
Interestingly, however, anxiolytic- and antidepressant-like effects produced by estradiol administration are attenuated by CB1R blockade , whereas estradiol administration increases AEA levels  or AEA signaling , possibly via downregulation of FAAH driven by an estrogen response element on the FAAH gene that suppresses FAAH transcription when bound by estrogen
So basically, estradiol has been known to have an anti-depression and anti-anxiety effect.
When estradiol drops (even in the monthly cycle), depression and anxiety can spike.
I was laid out by 24/7 rolling anxiety from perimenopause so count me in!
So...above, they found that estradiol blocks a cannabinoid called FAAH. FAAH eats up anandamide.
Anandamide is our "bliss" molecule...literally named after the Hindu goddess of bliss, Anand.
Estradiol directly governs that balance!
In fact, when they block the receptors for anandamide (CB1), the anti-depression/anti-anxiety effect went away from estradiol!
Goodness. This should be front-page news!
Check out the review on the woman who can't feel anxiety or depression (or pain) here or CBD and perimenopause anxiety.
That's one of 1000's of examples across the brain and body.
You're never going to guess what else can boost anandamide.
CBD and estradiol
In many ways, CBD and estradiol are partners in crime (health, actually).
They can have similar and interrelated actions.
Remember anandamide (AEA) above and FAAH which eats it up?
E2 stimulates NAPE-PLD and inhibits FAAH synthesis and directly stimulates the release of AEA from endothelial cells
This action was key to estradiol's anti-anxiety and anti-depression effects.
What about CBD?
From a study on stroke prevention (a bonus if you're worried about the old studies on horse estrogens):
CBD (center) increases circulating anandamide by inhibiting the catabolic enzyme FAAH and transporter AMT.
So...estradiol and CBD have very similar effects on FAAH (reduce) and Anandamide (increase) which has anti-anxiety and anti-depression effects among others (pain, sleep, mental health, etc).
Staying in the brain, let's look at GABA since it's tied with insomnia, anxiety, and other "symptoms" (but it's not that big of a deal, miss) of perimenopause.
Our data indicate that the estrogen may increase the number of GABA binding sites by direct interaction with the GABA receptor gene or genes involved in the metabolism of the GABA receptor.
The effects of estradiol are varied on GABA depending on the area of the brain.
In fact, we can think of estradiol as excitatory and pro-growth.
This may reflect the difference between the two estrogen receptors (plus that GPERS one):
ERα, which has a generally anxiogenic effect, ERβ, which has a generally anxiolytic effect, and the G-protein-coupled ER known as GPR30, which has been found to both increase and decrease anxiety-like behavior.
Anxiogenic means to create anxiety. Anxiolytic means to reduce anxiety.
So...ERa is excitatory while ERb is inhibitory in nature. Remember that for later when we look at what we can do to offset any negatives of estrogen.
As for CBD and GABA:
Finally, the anxiolytic effects of systemic CBD partially depended on GABAA receptor activation in the EPM model
You can read all about CBD and GABA for anxiety here.
Again, we could walk through almost any system in the body and find estradiol and CBD (via the endocannabinoid) effects.
Let's look to see if CBD can act as insurance against the risks (whether they bear out for bioidentical estradiol with progesterone) of supplementation.
Let's, start with breast cancer.
This is exciting!!!
Ligresti et al. demonstrated that CBD caused a potent and selective inhibition of breast cancer cell growth
What about estrogen specific lines of breast cancer:
A number of breast cancer cell lines, such as estrogen receptor (ER)-positive MCF-7, ZR-75-1, and T47D cells, and ER-negative cell lines MDA-MB-231, MDA-MB-468 and SK-BR3, are sensitive to the antiproliferative effects of CBD
The endocannabinoid system governs cell birth and death.
Cancer is a failure in that balance!
Let's look at how the body kills cancer (of any sort) and what research shows on CBD's effect there.
Basically, the body performs selective chemo and radiation.
It explodes the level of oxidation that kills the pre-cancerous cell.
That's why you generally can't take anti-oxidants when going through chemo and radiation.
Amazingly, CBD selectively supports this aim in the endocannabinoid system:
In the MDA-MB-231 breast cancer cell line, CBD leads to an increase in the generation of ROS, which finally results in an induction of apoptosis and autophagy
ROS is reactive oxygen species...oxidation!
Unlike radiation and chemo, it doesn't do this in surrounding, healthy tissue!
This may be one of the most impressive feats of CBD and really speaks to the system it supports.
Ask your doctor, but CBD may be used alongside chemo and radiation due to this effect.
Remember those triple-negative breast cancers from above?:
for triple-negative breast cancer, CBD effectively inhibited epidermal growth factor (EGF)-induced tumorigenic properties of these cancer cells by obstructing signaling pathways for EGFR, Akt, ERK, and NF-κB.
As for blood clots, CBD has a mild anticoagulant effect on thrombin and reduces the platelets needed for blood clots.
Some other considerations as "insurance" for estradiol supplementation besides CBD.
- Siberian Rhubarb -selectively targets the ERB receptor (even more than estriol). Buy here
- Organic soy - 90% of US soy is grown with glyphosate. Has to be organic.
- NAC - powerful support for glutathione. Buy here
- DHEA - new study showed it REVERSED epigenetic aging. Buy here
- Pregnenolone - (men and women) Buy here
- Curcumin - powerful across many systems especially on inflammation. Buy here
This is the insurance policy we mentioned above against Estradiol's pro-growth issues.
Let's look at alcohol... perimenopausal's favorite self-medication.
Estradiol and alcohol
Almost every one woman I know my age (in some stage of perimenopause) drinks. Daily.
Usually 2 glasses of wine a night during or after dinner.
What is this?
Alcohol is very interesting here.
Interestingly, it appears to be selective.
Caucasian women of European descent:
one in American women and one in European women--reported significant increases (p < 0.05) in estradiol levels in response to alcohol consumption.
Just as I suspected:
In the American women study, estradiol levels increased only with wine and not with beer or whiskey.
And alcohol in women on hormone replacement:
Estradiol levels were increased by 22 and 300% in the transdermal patch and oral studies, respectively.
The downside, of course, is an increase in breast cancer risk from alcohol.
If you do drink, seriously consider CBD to support liver detox and oxidation.
Check out CBD and glutathione or CBD and alcohol for more information.
Just know this may be your body's end-run to frantically make up for estradiol loss!
Speaking of estradiol loss…
Estradiol and weight gain
If you think estradiol isn't important to the body, look at what it tries to do when the levels drop at perimenopause.
We saw the alcohol effect above and the cholesterol effect is next.
What about fat?
Fat is one of the reserve generators of estradiol when it shuts off from the ovaries.
Consequently, the body makes more fat:
The absence of estrogens is a clue factor in the onset of cardiovascular disease during the menopausal period, which is characterized by lipid profile variations and predominant abdominal fat accumulation.
It's just weight gain as estradiol directly influences metabolism, energy, lipids, sugar, and a host of important functions.
Estrogens deficiency enhances metabolic dysfunction predisposing to DM type 2, metabolic syndrome, and cardiovascular diseases.
In fact, when the researchers knockout ERa receptors in studies, some of the effects are immediate:
Female and male mice that lack ERα have central obesity, have severe insulin resistance and are diabetic
And when they add estradiol back into the mix:
Studies mostly indicate a reduction in overall fat mass with estrogen and estrogen-progestin therapy, improved insulin sensitivity and a lower rate of development of type 2 diabetes.
Next up, the body's other great work-around for lost estradiol (and sex hormones in general).
Estradiol and cholesterol
We mentioned the study above where they were able to drop cholesterol in 100% of a small study simply by supplementing pregnenolone (the mother of all sex hormones including estradiol).
On the face of it, this is a strange result!
How could supplementing pregnenolone drop cholesterol?
Similar to what we saw above, the body panics.
All these hormones (estradiol, progesterone, DHEA, especially) are incredibly important to every working system in your body.
They then suddenly drop!
The body increases fat, craves alcohol, and...boost cholesterol.
Remember that pregnenolone is solely made from cholesterol... LDL, the so-called "bad" cholesterol in fact.
The body appears to be compensating for drop-in hormones by juicing up the raw material.
Check out the study here:
A final word on Estradiol
Look... work with your doctor but hopefully, you have some better guidance than I did when my numbers went to zero and I literally fell apart.
Some key takeaways from the imperfect research we have:
- Bioidentical hormones are key
- Progesterone can help improve the safety
- Skin is better but oral is not that far off (.0003 versus .0006)
- CBD, Siberian rhubarb, and organic soy can be protective
- Pregnenolone is not a bad supporting actor for the entire sex hormone cascade (up to 50 different hormones mind you)
We focus on CBD so why even go through all this trouble?
Because there are a million women who are exactly where I was a few years back in a very bad place with very bad information.
If I can save any of them from the 2-year trial and error hell I went through, it's all worth it.
Be well ladies.. we have to look out for each other now more than ever!
Master overview of CBD and anxiety pathways to look at various aspects we can directly affect.
Links to CBD and anxiety research with dozens of anxiety-specific topics.
Get specific links for CBD and Perimenopause symptoms and questions here.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.