It's been a three-year trip.
Not your best send-off with rolling panic attacks, pulverizing anxiety, and insomnia.
There were signs beforehand...even a few years back...but I hit a wall in January of 2017.
I had no warning from my general doctor. No warning from my OBGyn. Not even my mother or friends.
There was a general feeling that I was spiraling downward and it would take a few months to wrap my head around what's going on and worse yet...
A few years of fighting doctors and bad information around estrogen to get the right fix.
It's fascinating...progesterone (the counterweight to estrogen) is more accepted by our medical community but estrogen still has this specter of danger.
We'll dive into that as well.
You may end up a little angry and not just because reduced estrogen can lead to irritability and anger itself.
Let's get started so you can avoid a similar journey with these topics:
- Heading out - perimenopause is ALL about estrogen
- First crash - estrogen and mental health - bring on the clowns (I mean medicine)
- Second roadblock - estrogen and cardiovascular function - 2nd wave of medications
- Traffic jam - the pernicious effects of synthetic estrogens on proper care and research
- Detour - parsing out the topical versus oral estrogen debate
- Destination You - putting all the pieces together plus ways to protect yourself
Let's get started. This is mandatory reading for any woman in their mid to late 40's.
Heading out - perimenopause is ALL about estrogen
First, a lay of the land.
You have two primary steroidal hormones that are tied into every system of your body.
- Progesterone - key calming agent with powerful effects on the immune system, inflammation, sleep, and mood
- Estrogen - both a pro-growth, recovery side (alpha receptor) and a housekeeping side (beta receptor)
The two work together and even oppose each other in most pathways.
For example, they push (estrogen) and pull (progesterone) on the immune response.
The two literally shape your heartbeat timing and rhythm (see perimenopause and heart function).
Here's the important piece.
Progesterone starts dropping after its peak around age 20 and is at 50% by age 40!
That's why you see increased risk for autoimmune, histamine response, pain, inflammation, and other issues during your 40's and with a much greater impact on women.
Again, progesterone is a powerful regulator of our immune system. Big progesterone guide.
It's interesting...Mother Nature is a very efficient builder.
If she has existing pathways or machinery, she'll piggyback other uses for it.
Estrogen and progesterone are both dominant players with keys to every cell in your body so they've been given side gigs that touch on just about everything.
We'll see powerful examples of this below in the mental health section.
As for progesterone and immune response, during pregnancy, progesterone is ramped up partially to keep the immune system from attacking the amniotic sac which is actually constructed from the male's genes.
Otherwise, the body would attack it as a foreign entity and new research is pointing to low progesterone and premature births:
Estrogen is equally tasked with multiple responsibilities beyond reproduction.
Before we get into its importance, we need to understand its cycle going into menopause.
Unlike progesterone which continues to decrease in a slow steady manner, Estrogen remains strong and then goes into a roller coaster ride in our late 40's (47 for me, thank you).
In the US, there are about 1 million women entering perimenopause every year.
Of those 1 million women, here's the rough breakdown:
- 25% will have a debilitating transition
- 50% will have a difficult transition
- 25% will have a smooth transition
We're talking about hot flashes (smooth) versus rolling panic attacks and racing hearts.
I've looked at my particular experience (the unlucky first 25% group) here but that was written towards the beginning of the journey.
I had no idea then how much I would have to fight to get the right fix and that estrogen would be treated like Voldemort from the medical community.
My progesterone was addressed (by my 3rd doctor) finally and it really helped. Things were still not right though and no wonder….estrogen was in flux and/or missing.
You can view my brutal perimenopause journey directly through the lens of estrogen.
Let's take a ride, shall we??
First crash - estrogen and mental health - bring on the clowns (I mean medicine)
We have a whole review on estrogen and mental health but this is where I really got hit.
Keep in mind that estrogen can spike and drop like a yoyo during this period of time. See our review on why some women get hit so hard to see the research.
Here's the issue...estrogen is tied directly into powerful neurotransmitter pathways...the biggest one is serotonin.
Serotonin is usually called the feel-good neurotransmitter but that's not the whole story.
It's more like the "feel right" chemical...as in, feel correct in my body messenger.
Actually, serotonin is tied to ALL human behavior. We did a whole review on CBD and serotonin here because it's so interesting.
- Self-esteem? Serotonin
- Pain thresholds? Serotonin
- Stress response? Serotonin
- Sleep? Serotonin!
So what's the connection with estrogen?
You can think of estrogen as a pump in the chemical machinery of the body.
It pushes things along….including serotonin!
Estradiol is especially nurturing towards serotonin – it stimulates TRPH expression to ensure that enough serotonin is made and suppresses MAO A levels to prolong the longevity of the neurotransmitter.
Goodness...it boosts serotonin on the front end and slows the breakdown on the backend.
Our personal theory is that one contribution to a brutal perimenopause stems from a variant of the MAO gene where women break down neurotransmitters such as serotonin faster than the standard version.
Essentially, their systems rely more heavily on estrogen to keep neurotransmitters at peak form.
Then it leaves!
Downstream from serotonin is probably the most important player you've never heard of.
BDNF. Our brain's fertilizer.
It's literally holding back the damage that occurs in the brain and nervous system from trauma, chronic stress, infection, excess glutamate (brain's gas pedal), and anything that can damage the brain.
We can find BDNF lurking across the entire mental health landscape and even addiction.
In fact, the two common threads of drug relapse:
- Increased stress
- Reduced BDNF levels
Serotonin drives BDNF and when we dug deeper into how SSRIs work (till they stop due to tolerance), it was primarily about BDNF and its result...neurogenesis.
That's the go-to medication for women during perimenopause and beyond (till it builds tolerance). Go figure!
It's not just serotonin, our "feel right" transmitter that estrogen drives.
First, MAO also breaks down dopamine, our motivation and learning molecule.
Dopamine is tied to every mental health issue out there as well!
Then there's acetylcholine...the driver of both calm (rest and digest part of the nervous system) and cognitive function (alertness and focus).
In new research, it's the linchpin for dementia risk and ADHD. Nicotine fits nicely into its receptor as an example. Calm but alert.
Estrogen facilitates cholinergic neurotransmission in the septal–hippocampal pathway as evidenced by its ability to increase activity and mRNA of choline acetyltransferase
Brain fog. Confusion. Memory issues. All big symptoms with estrogen loss and peri or menopause.
See our review on CBD and dementia to dive deeper into that piece.
Again, estrogen keeps all neurotransmitters running at full speed.
Accordingly, estradiol facilitated neurotransmissions to GnRH neurons via both GABAA-R and glutamate/AMPA/kainate-R.
Goodness...everything you need to make a brain work.
So when your doctor says, "Your levels are fine for your age", remember...we want estrogen levels from when we were 20! This isn't about reproduction.
Let's take actual examples now.
Estrogen and depression
None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies–Depression Scale and 17-item Hamilton Depression Rating Scale,
Essentially, women in perimenopause were given estrogen and showed no depression.
The estrogen was switched for placebo and depression symptoms shot through the roof!
Estrogen and anxiety
Serotonin has a big part here since it's a stress buffer but GABA is the key immediate pathway for anxiety.
Let's get to the heart of it:
Estrogen calms the fear response in healthy women and female rats, according to the Harvard researchers
Specifically, research has shown that women trained on a fear-extinction task do better when the level of estrogen in their blood is higher.
Check out our anxiety guide.
Estrogen and OCD
A fascinating study blocked aromatase which converts testosterone into estrogen (yes, men have estrogen in the brain and it works the same as above).
The mice who had their estrogen levels dropped showed tail tell signs of OCD:
The extreme grooming and running patterns are two indicators of OCD in mice, and low COMT levels have been found in obsessive-compulsive men, say the researchers.
This is important because they only affected estrogen and were able to "create" symptoms as a result.
Again, we could pick almost any mental health issue and find an estrogen connection.
Here's the rub. Most women who start to display telltale signs of estrogen flux or dropping will be prescribed SSRIs or benzos.
SSRIs boost serotonin but they do it in one direction.
Remember that estrogen can also spike during perimenopause so that can lead to too much serotonin, a potentially dangerous situation called serotonin syndrome.
The other class that generally gets thrown at women is benzos. Valium. Xanax. Ativan. Klonopin. Also the range of sleep aids.
These carry a black box warning from the FDA regarding addiction and withdrawal.
They're not intended for over 2 weeks which doesn't match the years of perimenopause (not to mention decades of menopause).
I was put on Lexapro, valium, Xanax, Klonopin before all was said and done.
Weaning off of those was brutal (see How I weaned off benzos) even though the Lexapro was much worse.
We tried to research the prescription prevalence of these drugs by age and gender but our guess is the 45-55 age for women is a sweet spot for use.
See CBD versus benzos to learn more on how they work.
After this initial ramp-up of medications, we then turned to the heart side of things.
Let's go there now.
Second roadblock - estrogen and cardiovascular function - 2nd wave of medications
When you have rolling panic attacks and anxiety, it tends to affect your heart rate and blood pressure.
Go figure. Full review of perimenopause heart issues.
I would have a racing heart and spiraling blood pressure through the day and night.
My sleep was totally destroyed as a result of this and in combination with the SSRI which can drive insomnia.
They then slammed me on blood pressure meds.
My pressure would drop till a panic attack would throw me into the ER and they layer new meds on top.
I had your classic list:
- Hydroxychlorathiazide (diuretic)
- ACE inhibitors like lisinopril which increased my heart rate so then...
- Beta-blockers like metoprolol
I was a mess. I still had breakthrough racing heart and BP.
All of this went away with progesterone and estrogen.
I weaned off all the meds.
What on earth is going on?
We covered a great deal of this in our perimenopause and cardiovascular function review but some highlights, please.
Progesterone and estrogen literally shape the heartbeat itself.
Look at the effects of estrogen directly on heart function:
Heart palpitations are a direct result of lower levels of the female hormone estrogen, which leads to an overstimulation of the heart.
We’ve also discovered that estrogen plays a key role in explaining why blood pressure is lower in young women and higher in older women
Think of the main class, diuretics like hydrochlorothiazide. It's basically a salt pill.
It turns out that estrogen directly controls all fluid pressure levels in the body.
Not only blood pressure but also the pressure within your cells!
Dehydration. Electrolytes. Blood pressure. All tied to estrogen.
A big part of blood pressure is the flexibility or plasticity of the arterial walls.
Guess who's directly involved:
Estrogen is also a vasodilator and hypotensive agent, and can induce vascular relaxation by stimulating release of endothelium-derived vasodilatory substances (e.g., nitric oxide [NO]) or by acting directly on the vascular smooth muscle (VSM)
- Estrogen opens up vascular ways.
- Estrogen lowers blood pressure
- Estrogen stimulates nitrous oxide
- Estrogen directly controls potassium and calcium channels (calcium channel blockers are major class of BP medication) in the muscles that control vascular flexibility
We'll skip over the positive effects of estrogen on cholesterol, blood sugar, metabolism, and fat creation.
Keep in mind that estrogen is made from HDL cholesterol, the supposed "bad" cholesterol.
Increased cholesterol may just be a compensatory reaction to dropping steroidal hormones (testosterone has the same effect in men).
Get the calcium scoring scan to see what's actually "sticking" and then address inflammation and metabolic function which are the keys to arteriosclerosis.
Now, when you google "estrogen and heart health", you're going to see a mix of what we've discussed and lots of scary stuff as well.
There is so much misinformation or old information out there.
Most of it stems from a WHI study that basically scared women and their doctors silly back in 2001.
We went deep into estradiol's safety and those studies here.
The bIg issue is that they were all based on synthetic estrogen and/or estrogen combined with synthetic progesterone.
Lets' go there now as it was the first roadblock we had to pass to really get back in our bodies.
Traffic jam - the pernicious effects of synthetic estrogens on proper care and research
The vast majority of the medical profession accepts that all estrogens are the same.
Couldn't be further from the truth.
Synthetic (such as the majority of birth control) is NOT the same thing as bioidentical.
In their defense, they don't get much instruction on hormones and the pharma reps mirror this information.
Let's walk through the rollout of estrogen and then dissect the synthetic versus bioidentical.
First, we had Premarin which is essentially a horse estrogen that was the top prescription in the US at one point last century.
The problem is that we're not horses and although the chemical structure is similar, it's not identical.
The net result was an increase in risk for stroke and thrombosis (blood clots).
This was the big stir from the 2001 WHI study.
Then came the synthetic estrogens which are also common in birth control.
They are generally combined with synthetic progesterone because after all, it's all the same thing (and much cheaper to make on an industrial scale).
Let's look at that gigantic misnomer.
Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins.
Breast cancer was another concern with estrogen in all the literature.
Even after looking at the low risk of estrogen when combined with progesterone, we still couldn't find a study that was clean.
Our latest bout with the doctor centered around getting estradiol directly which is the standard form women's bodies have.
It took 3 doctors and 2 years to get the topical estrogen finally.
We were prescribed 80% estriol (E3) and 20% estradiol.
The problem is that estriol only spikes during pregnancy and otherwise, is metabolized away pretty quickly in the bloodstream.
Not exactly the normal scheme of things.
The reason naturopaths do this is to protect from the pro-growth side of estradiol by stimulating the Beta receptor.
We sent over study after study and finally got it to 50/50 between the two. The Dutch tests showed that progesterone was stable right in the middle of the range but estrogen was still low and I felt it.
The final piece was cream and gels versus oral bioidentical once that hurdle was cleared.
Detour - parsing out the topical versus oral estrogen debate
The problem is that we had lots of bad research engrained with our medical profession that's muddied with synthetic hormones.
You would think we would have learned our lesson:
- Hydrogenated oil (oil + hydrogen molecule) almost wiped out a generation
- Fake sugars (sugar plus chlorine) wrecks the gut barrier (see CBD and gut barrier)
- Synthetic CBD (called Epidiolex) has a slew of side effects that CBD isolate does not
The gels and creams were irritating my skin and so I bounced back forth between them and among areas.
It's also a real hassle to use since it affects sex, clothing, and just about everything.
That and the fact that the skin (aside from the labia which became irritated) just doesn't seem to absorb well (as my Dutch test bore out).
What we needed was clean research with bioidentical for BOTH estradiol and progesterone in an oral form.
We had to wait till 2019 for such research with the product Bijuva.
We covered this in detail at our oral versus topical estrogen review.
The two big concerns in the medical community are stroke/heart attack and cancer from a French study on oral versus topical
The problem is that the French study mixed in synthetics!
This risk was in the first year of use.
Bijuva (oral bioidentical estradiol and progesterone) went through the rigorous testing required for FDA approval and found no risk versus placebo.
In fact, some of the metrics were better than placebo which isn't surprising considering that estrogen (if clean) is vital for every pathway in the body.
On top of that, cholesterol, glucose, and the metabolic domain improved from oral estrogen and this does not show with topicals.
2018 to get resolution on a trainwreck wrought in 2001. This is insane when 1 million women are entering perimenopause in the US every year and 25% of them will be walloped (Hi, my name is Andrea).
My naturopath fought me on the oral estrogen which is interesting in itself.
So we went online to PushHealth and requested Estrace (bioidentical oral estrogen).
2 hours later, it was as the pharmacy after years of dealing with compounded gels and creams.
The effect was within a few days and extremely positive. That was 3 years ago!
I started with the .5 mg Estrace and pushed for non-cylcing (a full 30 days) since I no longer have my period.
The reason our bodies cycle is so that we can be fertile one week out of the month. That ship has sailed so I want all the other benefits of estrogen.
Testosterone (estrogen's counterpart in the male body) doesn't cycle!
I used the Dutch test to get my estradiol right in the middle of the range to match my progesterone levels!
The two work in tandem and are usually opposed so it's important they balance.
The amount of suffering I had to go through (almost didn't make it through the serotonin syndrome from Lexapro and anti-nausea combo) was unbelievable. That full story is here.
It was all totally preventable with bioidentical Estrace and Prometrium (bioidentical progesterone).
Decades of bad information is running millions of women down the same dead end.
It almost feels like a conspiracy against women but ignorance is an adequate substitute.
Now with the Bijuva data, there's nowhere for misinformation to hide.
Let's look at other tools to add protection.
Destination You - putting all the pieces together plus ways to protect yourself
We went through the steps of discovery:
- Progesterone - bioidentical
- Estrogen creams but with the weak estriol E3 as the dominant factor
- Estrogen with more estradiol (our primary estrogen - see estradiol review)
- Oral bioidentical estradiol (Estrace in my case) The Promised Land
Luckily, I skipped the whole diversion to synthetic land where really nasty risks lie.
My prescription for Estrace is about $3/month so it's not a cost issue.
So...are there tools to keep estradiol in a safe range.
Again, estradiol is pro-growth which is important (otherwise, you atrophy in the body and brain).
Too much growth is always the risk so how do we hedge?
Here are the tools:
- Siberian Rhubarb
- Vitamin D
Siberian Rhubarb is a very safe and researched supplement that's popular in Europe and finally coming to the US (you can get it at Costco now). Menopause 731 is the name.
Remember how our naturopath focused on E3 (estriol) as a protective measure because it focuses more on the Estrogen beta-receptor?
Siberian rhubarb is exclusively beta. It helps with the housekeeping responsibilities of estrogen so you see lots of benefits with hot flashes, sleep, mood, etc.
Not as much with vaginal and urinary tract with can atrophy when estrogen leaves the station.
That's why we have estradiol! Siberian just counters the growth piece so it doesn't get out of hand.
See our big review of Siberian rhubarb but this is the same theory (actually better) than using E3 estriol.
Vitamin D and estrogen
So many people are deficient in D plus absorption goes down as we get older.
Get your levels tested. Don't go by the ridiculous under 30 as deficient as that's based on bendy knees and rickets. Endocrinologists want us at 70-80 and higher.
This has huge implications for cancer, immune response, and even hormone function itself!
Vitamin D is actually a steroid (like estrogen and testosterone) we get from the sun.
See our big review on Vitamin D.
Fisetin and estrogen
Found in apples, fisetin has powerful effects on cancer and longevity.
We did a big review here but if excess growth is a concern (although Bijuva showed no hyperplasia - excess growth).
We love fisetin for its longevity effects as well and we cover it in the review.
Berberine and estrogen
Berberine is fascinating. It's an analog for metformin which has known longevity effects by stimulating a powerful system called AMPK.
AMPK basically tricks the body into thinking we're in hard times (famine, drought, lack of oxygen, etc) and the body tightens up the ship.
This has huge impacts on cancer but there's a curious connection with hormones directly.
Berberine (and metformin) help with hormone imbalance as seen with studies on PCOS (polycystic ovarian syndrome).
It's also very powerful with gut inflammation which acts as a thermostat for inflammation throughout the body and brain.
Remember that cancer detection and elimination is really a function of the immune system.
That brings up our next piece.
CBD and estrogen
We covered the effects of CBD and Turkey Tail on cancer.
CBD actually works within the system that balances other key systems including the immune response (cellular growth and death cycles).
CBD's greatest strength is that it operates like a feedback mechanism.
Cancer cells are a perfect example:
- Healthy cells with low inflammation - CBD has no effect
- Healthy cells with high inflammation -CBD reduces oxidative stress
- Cancerous or virally infected cells - CBD INCREASES oxidative stress
What on earth is going on here? Three different results are based on three different setups.
This is the immune system's natural way to kill off wayward cells.
Chemo and radiation are essentially massive doses of oxidative stress!
It's not just cellular death and birth cycles.
The other big risk based on synthetics...thrombosis or vein clots.
Endocannabinoids control Platelet Activation and Limit Aggregate Formation under Flow
Basically, a key endocannabinoid called anandamide is part of our natural system to keep clotting under control.
CBD boosts anandamide (see CBD and endocannabinoid deficiency).
There's one more piece of thought that's highly relevant to hormone replacement therapy.
One study (albeit, with synthetics) found that when women wait to replace hormones, there can be risks.
A fascinating animal study found that CBD could reopen this window.
We go deep into this research but hormone replacement affects endocannabinoid function and endocannabinoids (which CBD supports) drive the HRT improvements.
The full study on CBD and starting HRT late.
Lots of research is there on risks from letting hormones go down including dementia, heart, and more.
We're at the end of the journey. England is so far ahead of the US in giving women the real risk profile and choice over the bodies when it comes to estrogen.
In the next 3-5 years, you'll see an explosion of reports and information finally supporting the need for estrogen (bioidentical) for women in perimenopause and menopause.
In the last week, we saw an article in Forbes on women forced out of the workforce from age 45-60 when they should be at the top of their game.
Between our estradiol safety review, topical versus oral estrogen, estrogen and mental health, and progesterone reviews, hopefully, we're speeding this along to reduce suffering.
Be well. Take care of each other. Take care of yourself.
This glimpse into perimenopause is just the beginning. 'Dre's Story' offers our complete, research-rich journey into hormones, tools to feel better, and safety. The full Perimenopause Toolkit with new additions can be found Here. Please review so other can learn. Feeling better starts with understanding what is happening.
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.