Progesterone and Mood, Immune System, and Mental Health

by Indigo Naturals September 27, 2020

"Your levels are fine for your age".

That's the statement that came out of my doctor's mouth when I entered perimenopause hell.

That full story is here but it begs the question...why should we settle for an age-related decrease in progesterone (or estradiol).

Especially after you read this and just how integral progesterone is to every system in our body.

Unfortunately, our hormonal programming was designed 1000's of years ago when we probably lived to about 35.

Progesterone drops in half by age 40!

It then keeps dropping as we get older and when you see all its tricks in the body and brain, you'll start to understand why so many women pick up drinking (or drinking picks ups) in their 40's.

Alcohol boosts GABA (target for benzos), our calming neurotransmitter.

So does progesterone! We'll get into all of it below with a focus on why women are walloped by autoimmune, anxiety, and more.

You can thank your declining progesterone for this and while you're at it, thank that doctor and find another one!

These are the areas we'll cover:

A quick intro progesterone, your calming and protective blanket
Progesterone and immune response with implications for autoimmune
Progesterone and GABA - a key for mental health
Progesterone and sleep
Progesterone as a safeguard from estradiol - the yin-yang of the two
How to support progesterone as we get older (with an effigy to the 2002 WHO report)

Let's get started. You're about to have a whole new appreciation for just how essential the second fiddle (to estrogen) hormone can be.

Here we go!

A quick intro progesterone, your calming and protective blanket

Progesterone is one of the two powerful steroidal hormones that drive almost every aspect of a woman's body and brain.

Yes, men have progesterone and estrogen but at much lower levels.

In a woman's body, almost every cell has receptors for both progesterone and estrogen.

We'll get into their relationship below but finally, progesterone gets the spotlight.

Progesterone is a powerful player in reproduction with a management role during pregnancy.

In fact, it's often called the hormone of pregnancy.

Indeed, it rises during our most fertile parts of the cycle and drops if there is not a successful pregnancy.

Everything from preparing the uterus to reducing contraction before delivery (key to preterm labor).

Unfortunately, more medical field is primarily focused on this aspect of progesterone...making babies!

After my perimenopause ordeal, I would be so jaded as to say making babies is the extent of their concern for women's health. Again, that story is here but back to progesterone.

Mother Nature typically takes an existing chemical or pathway and piggybacks other functions.

Progesterone is no different.

A big part of its role during pregnancy is calming the immune response during pregnancy.

Progesterone (P4) is a vital hormone in maternal reproductive tissues and immune cells during pregnancy. As such, P4 is widely used in clinical interventions to improve the chance of embryo implantation, as well as reduce the risk of miscarriage and premature labor.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449726/

This is fascinating because it leads to very powerful effects throughout our lives and health.

Here's the deal.

Pregnancy is somewhat of a hostile takeover.

The amniotic sac is actually made from the father's DNA. It's essentially there to protect the fetus from the mother's body which views it as a foreign intruder.

In order for any of us to be here now, the mother's immune system has to be turned down or it will attack the amniotic sac.

What accomplishes this?

Progesterone!

P4 appears to dampen pro-inflammatory cytokine production, which consequently reduces T-helper subtype differentiation and proliferation (5–8). Furthermore, P4 blocks natural killer [NK] cell degranulation and, therefore, cytolytic function (9).

That's a shortlist of nasty attack agents from our immune system. They're designed to go after foreign bodies (us versus them).

A great deal of preterm labor may reflect insufficient progesterone to keep our immune system at bay against the amniotic sac.

This is why influenza and malaria can actually worsen during pregnancy since our immune system is turned down.

It's a trade-off. We've covered through our mental health reviews how an infection in utero can come back as mental illness later (see CBD and mental health).

The key takeaway is this…

Progesterone in general has a powerful calming effect on our immune system.

But that's not all.

In fact, we can think of progesterone as a calming agent in general.

It's very similar to the push-pull of our neurotransmitters: glutamate and GABA.

Glutamate is the "gas" pedal of brain activity. GABA is the "brake" pedal.

Estrogen is the pro-growth "gas" pedal hormone. Progesterone is the "brake" pedal hormone.

That's the context in which we'll really dive into why progesterone is so important regardless of your age (and what your doctor says).

Let's get started since we now know the "backstory" to progesterone in pregnancy.

What about the other roughly 1000 months we're not pregnant?

Progesterone and immune response with implications for autoimmune

As we mentioned, we've just wrapped up our mental health review with CBD.

The new direction for mental health is focused on the immune system.

We know that sounds bizarre but just watch over the next few years.

Anxiety? Check.
Depression? Check
Schizophrenia and bipolar? Check.
Dementia?

Maybe more than all the rest!

In fact, the little AB particles that accumulate and form amyloid plaques?

They're tiny assassins in our brain's immune response to bacteria.

There is a fascinating TED talk we reference at our CBD and dementia review which walks through all the new research.

This is a perfect seque into autoimmune disease.

Forget diabetes and arthritis (if you can), all the major diseases are turning up with elements of autoimmune.

Including dementia?

What about gender and age? Do those have an impact on autoimmune?

Women are hit hardest by autoimmune across the board.

Roughly 80% of autoimmune diagnoses are for women.

For Lupus, it's 90%!

Remember how we said that progesterone drops by 50% at age 40?

Now compare that with this fact:

Rheumatoid arthritis (RA) can begin at any age but has its peak between ages 30 and 55

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238350/

The backend coincides nicely with the end of perimenopause.

Remember how progesterone's main starring role is during pregnancy?

We would expect to see an impact there on existing autoimmune diseases if our theory is correct.

Is there one?

During pregnancy many autoimmune diseases go into remission, only to flare again in the early post-partum period.

https://clinicalmolecularallergy.biomedcentral.com/articles/10.1186/s12948-016-0048-x

What about the front end...before progesterone really comes into play during puberty?

The female predominance of autoimmune disease is highlighted by the fact that the onset of most female-dominant autoimmune diseases occurs following puberty.

https://ndnr.com/womens-health/female-dominant-autoimmunity-the-role-of-progesterone/

Symptoms can even fluctuate during the cycle.

Finally, what about progesterone supplementation?

More importantly, what about bioidentical progesterone since the profile is significantly different from the synthetics progestins so many women are on (HRT and birth control).

Don't take our word for it:

Observational studies suggest that in menopausal women, estrogen and progesterone use may be associated with lower breast cancer risk compared to synthetic progestin.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960754/

The studies reviewed suggest bioidentical progesterone does not have a negative effect on blood lipids or vasculature as do many synthetic progestins, and may carry less risk with respect to breast cancer incidence.

https://pubmed.ncbi.nlm.nih.gov/17217322/

And on and on.

Remember how we said our medical field is really done with women's health after birth?

After everything we looked at above, we can't find a trial on bio identical progesterone and autoimmune progression.

There's one noted for synthetics but we can't use that as progestins are not progesterone just like hydrogenated oil is not oil and synthetic sugars are not sugar.

Even more so with progesterone, a critical workhorse of our biology.

Now, it probably has nothing to do with autoimmune being a billion-dollar business (every commercial you're likely to see is autoimmune) with price tags in the 10's of thousands per year. Forever!

But...it's an interesting question.

What we do know is that autoimmune:

generally starts with puberty
Goes into remission during peak progesterone (pregnancy)
Gets worse as progesterone fades (age 30 -50) into perimenopause
Hits women at almost a 4:1 ratio.

The more interesting piece is this:

The ratio of occurrence within women has been increasing over the past decades.

There's an environmental effect as well.

Let's get to the heart of what research is showing for autoimmune.

The issue may lie in the gut barrier (and eventually, the blood-brain barrier for mental health and dementia).

All roads lead to Rome and the gut is our new Rome for health.

Why is the immune system overreacting more and more with time?

Genetics haven't changed every decade.

There are clear associations between autoimmune a range of environmental factors:

Susceptibility to autoimmune disease can be impacted by environmental factors [11] which encompass everything around us including the air we breathe, the water we drink, the food we eat, synthetic and natural chemicals, microorganisms, radiation, industrial by-products, and physical factors

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302961/

We have to go to the root of the problem. The gut!

This is where things initially go wrong leading to issues around the body.

Let's follow the traces.

Your gut lining is the only barrier between your inner world and the outer world via food and all the bacteria, viruses, and more that hitch a ride.

Speak of Trojan Horse...literally into your body!

There's a very complex and powerful system there to only let in good things (nutrients, etc.) and not bad (bacteria, viruses, etc.).

The trillions of "good" bacteria called the microbiome to make up the first defense...a thick layer of living shield essentially.

The second layer is your gut lining, a marvel of design with a series of protected gates.

Here's the issue...so much of our modern world breaks down this guard.

Chemicals. Pesticides. Fake sugars. Artificial colors. Medications. Drugs. Alcohol.

Bad bacteria start to get through and travel around the body until the immune system detects them and attacks them.

If this chronic, it can set up a constant drumbeat of war and there's always collateral damage.

Check out CBD and autoimmune to look at the supporting research but progesterone figures into this.

Just look:

Progesterone decreases gut permeability through upregulating occludin expression in primary human gut tissues and Caco-2 cells

https://www.nature.com/articles/s41598-019-44448-0

Occludin is the glue for tight junctions in our gut wall!

Goodness. This hormone has been dropping since age 18.

Check out CBD and gut barrier.

Okay...we went straight to illness. Autoimmune.

There's a whole spectrum of the immune response which is equally important.

The worlds of inflammation and histamine response.

Progesterone has powerful effects on both and since inflammation is tied to almost every modern disease, this is very important.

There's tons of research that shows progesterone calms immune response such as this one following brain injury:

Progesterone given after traumatic brain injury (TBI) has been shown to reduce the initial cytotoxic surge of inflammatory factors.

https://pubmed.ncbi.nlm.nih.gov/15932748/

Check out CBD and neuroinflammation to see why this is important for mental health.

Another study looked at progesterone's effect after the immune system stimulation by bacteria signatures (called LPS).

In conclusion, progesterone exhibits pleiotropic anti-inflammatory effects in LPS-stimulated BV-2 microglia by down-regulating proinflammatory mediators corresponding to suppression of NF-κB and MAPK activation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117574/

Again, calming immune response and you now know why from above (protecting the fetus as a "foriegn" entity).

Most of our modern diseases bare the marks of too much or chronic inflammation.

Then there's histamine...a part of our immune system that can go haywire.

Many women find that they suddenly can't eat certain foods or use makeup.

Histamine responses increase through our 40's as progesterone drops.

Histamine not only controls our allergic response but is a powerful neurotransmitter in its own right with governance oversleep (or the lack there of), anxiety, and more.

We did a big review of histamine and insomnia.

Progesterone's effect is prominent there:

In contrast, progesterone (100 pM to 100 nM) had a significant inhibitory effect on histamine secretion induced by IgE-DNP in PMCs from both male and female rats

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417946/

Interestingly, the effect was much more pronounced in females than in males!

So...if you're suddenly having trouble with chili peppers or mascara, progesterone may be the root cause there.

Let's now turn our attention to the brain!

Progesterone and GABA - a key for mental health and sleep

My first introduction to dropping progesterone was increased anxiety and eventual panic attacks.

This was around age 44-46. I then hit a wall at 47 and that story is here.

There are progesterone receptors throughout your brain!

Let's look at just a few pathways since its effects are everywhere.

We'll focus on GABA and inflammation.

GABA is the main "brake" pedal for our nervous system. It's the target of benzos until addiction and tolerance take over.

See CBD versus benzos for anxiety or CBD for GABA.

GABA and its opposing force are critical across every major mental health issue.

It's obvious for the following:

Anxiety (see GABA and anxiety)
Panic attacks (see GABA and panic attacks)
PTSD (see GABA and PTSD)
OCD (see GABA and OCD)
ADHD (see GABA and ADHD)
Seizures

We go through the mechanics of how these work with CBD which works like a feedback system for GABA function.

But it's really glutamate that's the new shining star in mental health (along with immune system hyperactivation).

The two are linked.

Our immune system managers called microglia would release glutamate if stimulated.

Glutamate is a tricky substance and there are many safeguards built in to keep it in range.

As the brain's "gas" pedal, we need it power all brain activity but too much is highly destructive.

It will literally kill neurons and reduce brain mass.

That comes into play for the following:

Schizophrenia
Bipolar
Depression
Autism
ADHD

Holding glutamate back is GABA so what's the connection with progesterone?

Progesterone breaks into a chemical called allopregnanolone.

A quick seque is needed.

There's now a blockbuster drug for postpartum depression that costs $25K and requires a night in the hospital.

It's a total game-changer though for depression.

How does it work? It's a synthetic version of allopregnanolone. You can boost allo by taking pregnenolone for under $10 (buy here).

Here's why allo matters:

Allopregnanolone is a potent positive allosteric modulator of GABA action on the GABAA receptor. Allopregnanolone slows the rate of recovery of the GABAA receptor from desensitization and possibly increases the rate of entry into fast desensitized states.

https://www.sciencedirect.com/topics/neuroscience/allopregnanolone

It boosts GABA levels and function!

Progesterone can literally change the shape of GABA receptors to affect how they work with powerful effects:

Animal studies have shown that progesterone can change the shape of receptors present in the cerebellum, which forms connections with the limbic and prefrontal cortices, which are responsible for controlling emotion and behaviour.

https://www.newscientist.com/article/dn20122-why-women-get-anxious-at-that-time-of-the-month/#ixzz6XZPsC3jr

Just emotion and behavior. That's all.

That's just one example but you can check out our GABA review or our Glutamate review for mental health.

There's just so much research.

The key is this...glutamate by itself or as a result of immune system hyperactivation is a direct insult to proper brain function.

Then there's the other side. Neurogenesis.

That's a fancy term to reflect the process of repairing, rewiring, and growing brain tissue and connections.

BDNF is the star there as the brain's fertilizer.

Progesterone's effect there?

Progesterone Increases the Release of Brain-Derived Neurotrophic Factor from Glia via Progesterone Receptor Membrane Component 1 (Pgrmc1)-Dependent ERK5 Signaling

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423611/

All roads are pointing to neurogenesis across the spectrum of mental health issues.

Check out CBD and neurogenesis or CBD and BDNF to learn just how important they are.

Our big review on GABA really gets into how important it is.

Let's turn to inflammation.

We already saw above how progesterone has powerful anti-inflammatory effects.

This is so important for mental health!

We did a full review at our CBD and neuroinflammation review or CBD and inflammation.

Just one example:

More and more studies suggest that depression and/or bipolar disorder are accompanied by immune system dysregulation and inflammation, and high levels of cytokines. Inflammation has been found to trigger depression, almost like an allergic reaction.

https://www.psychologytoday.com/us/blog/expressive-trauma-integration/201905/inflammation-and-mental-health-symptoms

There's a great explanation here of the gut-brain connection and we already showed how progesterone affects the gut!

Again, we could go and on but we've covered those in detail at our CBD and mental health for more reference.

We have to consider sleep with mental health so let's go there now.

Progesterone and sleep

We can piggyback right off GABA and mental health for sleep.

The two are mutually entangled!

In fact, a study just came out that sleep quality is the biggest determinant for dementia. End of story.

Another study showed MRI scans of sleep-deprived people and the brain activity was indistinguishable from major anxiety.

Guess what most of the sleep aids are based on?

Stimulating GABA!

Check out CBD and sleep to get deep into research.

You see the effects of progesterone across the spectrum.

Monthly cycles:

Immediately before bleeding begins, a woman’s progesterone levels dip dramatically, which is why some women can find it really difficult to get quality sleep in those “PMS” days.

https://www.yalemedicine.org/stories/women-are-your-hormones-keeping-you-up-at-night/

During pregnancy, when progesterone explodes higher, drowsiness is a known symptom.

One study looked at progesterone supplementation directly for sleep:

Under placebo, blood sampling procedure was associated with marked sleep disturbances, which were considerably reduced under progesterone treatment: mean duration of wake after sleep onset was 53% lower, slow-wave sleep duration almost 50% higher, and total slow-wave activity (reflecting duration and intensity of deep sleep) almost 45% higher under progesterone than under placebo (P ≤ 0.05).

https://pubmed.ncbi.nlm.nih.gov/21289261/

Wow...improvements across the entire suite of sleep related metrics.

I take my progesterone (bioidentical oral) before bed or if I wake up in the middle of the night and its like a benzo without the addiction.

Big surprise here:

Progesterone stimulates benzodiazepine receptors, causing the release of gamma-aminobutyric acid (GABA), a sedating neurotransmitter that can potentially facilitate sleep

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607064/

But without the addiction, normalization, tolerance, and withdrawals!

In fact, in one conclusion, they found it was:

" acting as a "physiologic" regulator rather than as a hypnotic drug"

This is important...we don't want a sedative effect. We want our sleep from when we were young!

Then there's a whole relationship with cortisol.

It's not just our primary stress hormone but a key driver of alertness at lower levels.

There's a cycling of GABA (sleep) and cortisol (wake) along with histamine that governs our daily sleep pattern.

Cortisol and progesterone are both made from cholesterol so if we have too much stress, we're not getting enough progesterone.

It's a vicious cycle. You can think of progesterone as a buffer from stress and/or essentially being eaten up by stress response (cortisol takes priority).

Again, check out the sleep review with lots of research on various components including progesterone.

Let's turn to progesterone's relationship to estradiol.

Progesterone as a safeguard from estradiol - the yin-yang of the two

In the body, there are many "duo's" that oppose each other to find a balance.

The balance may shift as needed but comes back to midline.

Estrogen and progesterone have such a relationship in many pathways across the body.

We're not knocking estrogen...it's as important to a woman's body as progesterone as you can find out from our estradiol review.

In fact, the drama of perimenopause is from flux of estrogen and estrogen drives serotonin, our master regulator of all human behavior!

That being said, progesterone is showing an ability to keep estradiol in check which is important.

Estradiol is pro-growth. Again, very similar to glutamate.

You need growth to keep up with the insults of daily function down here on this Earth.

For example, estradiol boosts serotonin, our neurotransmitter that guides ALL human behavior.

A side hustle for serotonin is that it boosts BDNF, our brain's fertilizer which is needed for brain and nerve repair.

In fact, this is how SSRIs even work for depression when they do (until they normalize) and after we did our big review on magnesium, we're wondering if that's really their trick.

See how SSRIs really work or magnesium for mental health.

Growth is needed...it's the offset to inflammation, excess glutamate, hyperactivation of the immune response, etc.

Too much growth is bad!! That's the dreaded cancer link for estrogen.

It turns out that progesterone has a protective effect on this attribute of estrogen.

There are two main areas where pro-growth can be trouble:

Breast tissue
Endometrium (uterus lining)

Estradiol thickens the lining. Progesterone thins it. Yin Yang.

As Cleveland Clinic puts it:

When the endometrium is no longer shed, estrogen can cause an overgrowth of cells in the uterus, a condition that can lead to cancer.
Progesterone reduces the risk of endometrial (uterine) cancer by making the endometrium thin.

https://my.clevelandclinic.org/health/treatments/15245-hormone-therapy

For example if estradiol is used:

oral micronized progesterone provides endometrial protection if applied sequentially for 12-14 days/month at 200 mg/day for up to 5 years;

https://pubmed.ncbi.nlm.nih.gov/27277331/

As for breast cancer, be careful about what type of progesterone you are taking. The synthetics ARE NOT progesterone and yet they're handed out like candy.

The largest study to date looked at the difference:

It showed the same results as the WHI in women using synthetic progestins, that is a 26% increased risk for invasive breast cancer. But, it showed a 10% decreased risk for breast cancer in women using progesterone – a 10% decrease!

https://imcwc.com/html5-blank/progesterone-the-breast-cancer-shield/

We covered this for synthetic estrogens in detail at our estradiol review.

That's only cancer (only not being appropriate).

There's an interesting review of oral, bio-identical estradiol and progesterone combined showing no risk for excess growth with the new Bijuva drug. More here as we had to fight to get oral for both.

Estrogen and progesterone work to shape most (if not all) pathways in the body.

In our review of CBD and heart palpitations, we show how they literally shape the architecture of the heartbeat!

Again, if you drill into any given pathway or tissue (bone, brain, heart, etc.), you'll find a carefully choreographed dance between the two.

It's beautiful really. Until they both drop!

Check out our review on why some women are walloped by perimenopause.

Let's look at support!

How to support progesterone as we get older (with an effigy to the 2002 WHO report)

If our healthcare system cared about women, they would test their progesterone and estradiol levels annually from puberty or at least age 25.

They don't and if you go to a doctor at around age 47 with rolling panic attacks and racing heart, they'll likely tell you "Your hormones are fine for your age".

We weren't designed to live past 35 really, so this is a newer phenomenon but it's being sped up by our modern life.

Chronic stress and cortisol are known to deplete progesterone (and also GABA).

Cortisol is our main stress hormone (see CBD and cortisol), and interestingly, it's made from the same raw material as progesterone (cholesterol).

Mother Nature favors stress response since it implies danger over steroidal hormones (reproduction can wait till we're out of danger).

If we're chronically making cortisol, progesterone levels will suffer.

Too stressed out for too long. Sound familiar?

Pregnenolone is interesting since it's the primary driver of progesterone production (read the review here).

Then there's stress reduction (see Magnesium glycinate, CBD and stress, and NAC).

In the end, get a Dutch test and see how your body is processing estradiol and progesterone (along with a range of metabolites).

Bioidentical is night and day different from the synthetics (progestins and progestins) that millions of women are on.

The research is very clear there.

During my brutal perimenopause, progesterone was a complete game changer while estrogen did its roller coaster ride.

This glimpse into progesterone 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.