Is Progesterone the Key to Mast Cell Activation?

progesterone and mast cell histamine 

We learned the hard way…over 2-3 years.

The full story is here but perimenopause sent the founder reeling and so much suffering could have been avoided with one simple fix.

Supporting progesterone!

We'll look at the how's and why's below but for any woman over 40, progesterone is the first place to look if you suddenly can't eat certain foods or use certain cosmetics.

The interaction of estrogen and progesterone directly affects this question and we'll look at their very different trajectories over life.

We have a massive review of progesterone for immune, sleep, and mental health but our focus here is on histamine and mast cell activation.

These are the topics we'll cover:

  • A quick intro to mast cell activation and histamine
  • Progesterone and estrogen's effect on mast cells and histamine
  • The progesterone head-start out the door
  • Estrogens is everywhere!
  • How to support progesterone when out-gunned
  • Other tools to calm mast cell activation

Let's get started. This question keeps affecting younger and younger women and you'll see why below.

A quick intro to mast cell activation and histamine

For people with MCAS, this may be old hat but let's give a quick recap so that the rest of this review makes more sense.

First, it's important to understand that the entire histamine pathway sits squarely within the immune system.

Mast cells (named for their engorged look from a german root word) are the armory for histamine and a range of different inflammatory agents.

They are really the forward guard…early warning system.

If they detect foreign entities (bacteria, viruses, chemicals, etc), they release histamine which is tasked with getting the interloper OUT of the body FAST!

Hence, the common allergic reactions:

  • Rash
  • Itching
  • Quicken heart rate
  • Vasodilation (expanding arteries/veins)

We have a massive histamine guide (really interesting what it does in the brain and gut) but within our immune context, it's all about responding to disturbances from outsiders.

Beat cops.


Dre's Story - Perimenopause Survival Guide


Early infection, trauma, and stress can hyperactivate our immune system and that includes mast cells/histamine but the real power players are…steroidal hormones. Learn about that here.



can early trauma affect histamine and mast cells


Let's go there.

Progesterone and estrogen's effect on mast cells and histamine

Every cell in your body and brain has receptors for progesterone and estrogen.




how do steroid hormones affect mast cells


Think about that. This is not just about reproduction.

  • Bone
  • Brain
  • Heart
  • Gut
  • Immune system
  • Mast Cells!

Generally speaking, estrogen boost immune response (mast cells more active) and progesterone calms the immune system (mast cells less active).

Don't trust us...

Estradiol activates mast cells via a non-genomic estrogen receptor-α and calcium influx


Progesterone inhibits mast cell secretion

The question…is why?

This gets interesting.

It comes down to the amniotic sac!

Mother Nature generally likes to multi-task existing pathways in the body. That's why medications can have weird side effects and knock-on effects.

The amniotic sac is actually made from the father's DNA…it's a hostile takeover!  Nature's not always pretty.

The immune system sees this foreign entity and tries to attack it. Progesterone is the buffer there and it basically suppresses mast cell and histamine response during pregnancy.

Progesterone spikes during pregnancy and turns off the early detection system.

You see a range of weird responses that result:

  • Autoimmune diseases can go into remission
  • Mental health issues can calm down (see brain inflammation)
  • Histamine response can spike during part of the cycle when progesterone drops

In fact, low progesterone is now regarded as a primary driver of premature births (the immune system is winning).

The progesterone group showed a significant reduction in the rate of preterm birth before 33 gestational weeks

So…what's the problem with progesterone keeping estrogen balanced in our mast cell activity level?

I'm sure your OBGyn explained this to you in your 30's. Not!

The progesterone head-start out the door

We have a huge review of why 25% of women get hit with debilitating (yes..that's the word they use in NIH study) perimenopause.

We just weren't designed to live past roughly 35 (our deep deep ancestors rarely did).

Our progesterone drops to about 50% by age 40!

It starts this deep dive early 20s and continues down beyond 40 and continues to almost nothing.

Estrogen, however, remains pretty stable until the late '40s (for most women) then goes through a roller coaster ride spasm (perimenopause) which can feel just brutal.

Keep in mind that estrogen drives serotonin (our master mood and stress manager)...all human behavior really.

Progesterone drives GABA, our nervous system's brake pedal, and key to sleep, anxiety, and more.



support gaba for histamine


The mismatch is that progesterone drops much more quickly than estrogen which is a big problem across almost every pathway but especially histamine and mast cell activity.

You start to see the telltale signs of mismatch during our 40s.

  • Allergic reactions
  • Autoimmune
  • Sleep issues
  • Gut issues and food sensitivity
  • Anxiety and panic attacks
  • Heart racing and blood pressure
  • Metabolic problems
  • Arthritis and pain issues

Check out the progesterone guide or our estrogen and mental health guide.

Just an example with MCAS…DAO, the enzyme that breaks down histamine in gut is all the rage for MCAS activation.


  • Estrogen stimulates mast cells to release histamine and down-regulates the DAO enzyme that clears histamine. At the same time, histamine stimulates the ovaries to make more estrogen. The net result can be a vicious cycle of estrogen → histamine → estrogen → histamine.
  • Progesterone stabilizes mast cells, up-regulates DAO, and can therefore reduce histamine.

Love her stuff by the way!

This is if everything goes well…but there's more to the story these days!

Estrogens are everywhere!

There is another wrinkle to the whole story.

Naturally, progesterone is fleeing the scene long before estrogen. This leads to a lot of talk around "estrogen dominance".

Really, it's progesterone inferiority!

That's in a world without plastics, pesticides, hormone disruptors and more in our food, skincare, and everywhere!

We have many sources of extra estrogen that we're swimming in daily.

Just a few examples..

Phytoestrogen in food - essentially plant-based sources of estrogen (such as soy)

Hormone treatment in animal sources of food:

Environmental estrogens can be found in a wide variety of foods: phytoestrogens occur in plants such as clover and soy, while mycoestrogens are food contaminants produced by fungi. Meat, eggs and dairy products from animals given exogenous hormones contain relatively high concentration of estrogens

Great so that's both plant and animal sources if not organic.

Then there's plastic. Yes, that Starbucks cup!

In a recent study, researchers analyzed more than 450 plastic products such as baby bottles, deli packaging, and flexible bags and found that more than 70% of them released chemicals having estrogenic activity

That's BPA and but same holds true for lot of chemicals.

But it doesn't stop there.

What about PFOA, the forever chemical that we all have now in our bloodstream and it's even showing up in cord blood for newborns?


PFOA can result in the endocrine disruption by disturbing the functions of growth and sex hormones, including activating the estrogen receptor (ER) and inducing ER-mediated transcriptions in cells

Goodness…estrogen dominance indeed.

This might speak to why 20 year males today show average testosterone levels at half the level from just 20 years ago!

See our testosterone review to see why this isn't just about libido and muscles.

Then, there's the crazy move to linoleic acid (seed oils) as our primary fat source since the '70s (directly tracks obesity, diabetes, and testosterone drops).

Go figure..

The observed estrogenic effect following linoleic acid treatment suggests that this fatty acid could possibly act on the estrogen receptors with enhancing the endogenouse estrogen levels.

Ladies (and men)'ve been swimming in estrogen while progesterone was already on the way out naturally.

That's why MCAS and most immune diseases affect women at an 8:1 clip compared to men.

So…how do we buffer this onslaught (and it is that).

How to support progesterone when out-gunned

Before we started progesterone, we couldn't eat half of the menu, were popping DAO like it was candy, and avoided all cosmetics/sunblock, etc.

That has completely gone away and eating peppers is no issue now! Spicier the better (which matches longevity studies on capsaicin).


Perimenopause book for women


A few notes.

First, get tested. The Dutch Test is the best to determine how your body is actually metabolizing hormones.

Bioidentical is a must and if your doctor doesn't know the difference between synthetics (progestins) and the real stuff, you may need a new doctor.

One (of many) pathway examples:

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.


Remember that cancer and blood clots drove the fear train that a 2001 study caused which drove millions of women to drop HRT.

Progesterone (bioidentical)...33% reduction in cancer risk in combination with estrogen.

We also looked at oral safety at the Bijuva review.

Prometrium is a prescription option for bioidentical progesterone. Estrace is the equivalent for estradiol.

Remember, they oppose each other in many pathways and balance is the key.

The Dutch Test helps you dial this in since everybody is different. For example, some women breakdown their own steroids quicker or slower depending on COMT genes.

Just don't trust the…"Your numbers are fine for your age" if you're not feeling well.

The histamine response is a canary in the coal mine! This a great signal that progesterone is outgunned.

Test and adjust with bioidentical.

The founder takes progesterone at night (incredible for sleep) and estradiol (Estrace) in the morning.

This matches our natural cycle as progesterone drives GABA, the key to sleep, and estradiol is generally pro-growth/repair and stimulating.

Vitamin D is a steroid as well and it manages the function of both estradiol and progesterone.

Endocrinologists are aiming for 60ish ng/ml. Get tested and support as needed.

We have a huge Vitamin D guide.

Other tools to calm mast cell activation

We created a Top 10 Tips guide for mast cell support but the quick takeaways.



how to calm mast cell activation


We have deep dives on all of these but a quick recap.

The prerequisites:

  • Can't build tolerance (cause immune system to rebound as a result)
  • Can't have knock-on effects like ripping acetylcholine (like benadryl & Tylenol PM)
  • Shouldn't cause drowsiness or impact waking hour function

Okay…that leaves a few options. Here they are.

The highlights…

Magnesium glycinate and mast cells

Mag is a powerful wet blanket on stress and inflammation.

When mag goes down, mast cell activity goes up!

These results clearly indicate that Mg deficiency induces the emergence of mast cells around portal triads of the liver in Sprague-Dawley rats.

Mag is also a key rate limiting factor for DAO (which breaks down histamine in the gut).

Glycinate gets across the blood brain barrier best.

We take 3 x 100mg daily for stress response and migraines. More on magnesium glycinate

CBD isolate

We have a whole review on CBD and histamine or CBD and MCAS but the quick takeaway.

Together, the results suggest that CBD may induce activation of PPARγ in mast cells leading to secretion of G-CSF and consequent MDSC mobilization.

Basically, CBD triggers a key anti-inflammatory pathway (PPAR) which boosts the pathways that "resolve" or calm mast cell activation.

MDSCs are the "off" switch for mast cell activation.


Our data showed that activated PPAR-γ has the potential to alleviate food allergies by enhancing intestinal mucosal integrity and tight junctions.

This is the switch you want to throw when mast cells are running amok and CBD isolate has the finger on its trigger.

One note…the kind of CBD is critical. Full or broad spectrum CBD can actually trigger mast cell activation as we found out the hard way when we started this journey.

Hormone support

We already went through the powers of progesterone. We have a whole review on why progesterone is so critical to histamine response.

Get tested!

Support with bioidentical as needed. 


Prometrium is an RX option for bioidentical support. Progesterone works hand-in-hand with estradiol which depends on where you are (pre, perimenopause, menopause).

Either way, progesterone starts dropping much earlier (50% by age 40) than estradiol and hence…the mast cell issues!

Mast cell activation is the canary in the coal mine, so it's important to catch this early.

  • Brain
  • Heart
  • Bone
  • Organs
  • Gut

Every cell has estradiol and progesterone receptors.

For men, testosterone is equally important (and dropping). It's more immunomodulatory which means its effects are more nuanced. Still important to test and support.

Big guides:

Speaking of steroids.

Vitamin D

Vitamin D directly manages the immune system response including mast cells.

Let's put a point to it:

Late mast-cell activation leads to the release of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α. Vitamin D is required to maintain the stability of mast cells, and Vitamin D deficiency results in mast cell activation.

Get tested and aim for 50-70 ng/ml. We have a whole review on Vitamin D but like steroidal hormones, mast cell activation is just the tip of the iceberg for effects with 1000's of processes dependent on D including vital DNA repair processes.

Let's now turn to tuning up the immune system.

Medicinal mushrooms

Mushrooms are powerful players to dial in our immune response.

Certain species can literally reset our immune "setting" from TH1 to TH2…from hypervigilant to balanced.

For example…Chaga species:

The in vivo mast cell-stabilizing activity was also found only in EE and DF whereas the activities to suppress Th2 and Th17 immune responses and cOVA-specific IgE production in the small intestine were observed in all three treatment regimens, implying that inhibition of the mast cell function by lipophilic compounds was vital for the therapeutic effect.

Let's translate the Klingon.

Basically, chemicals in the chaga mushroom not only calmed mast cell activity but suppressed the hyperactivation of the entire immune setting in the gut.

Remember, the gut sets the inflammatory state for the body and brain since it's the site of first contact with most bad actors (bacteria, fungi, etc in GI tract).

That's just one example…of many!

Review of medicinal mushrooms.

Next up…another endocannabinoid.


Where CBD acts as a feedback support when our endocannabinoid system is exhausted, PEA is a naturally occurring backup player.

It supports anandamide (our primary inflammation calming agent) when it's outgunned!

The net results:

PEA is produced and hydrolyzed by microglia, it downmodulates mast cell activation, it increases in glutamate-treated neocortical neurons ex vivo and in injured cortex, and PEA levels increase in the spinal cord of mice with chronic relapsing experimental allergic encephalomyelitis.

Goodness. In this example in the brain…

  • PEA is made by glial cells (immune sentries in the brain).
  • It directly calms mast cell activity
  • It supports the repair of damage
  • It responds to allergic disease states

You can see similar effects across the body (skin, gut, etc).


More at our PEA guide.

Goes to show you how important the endocannabinoid system is for balance.

Okay…that's our toolkit for histamine. Deep dives on each of those.


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. 

Dre's Story - Perimenopause: A Surivival Guide


Related Research:

CBD and PEA for mast cells

Natural mast cells stabilizers

CBD women and histamine


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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.


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