Transcript from my April 2019 presentation about endometriosis, LPS, and immune dysfunction. Click here to view the presentation slides with references.
Here are a couple of things that we know quite confidently about endometriosis.
- It’s an inflammatory disease.
- It’s dependent on estrogen.
You all know about the second point. Estradiol is strongly stimulating to endometriosis and that’s why part of the conventional medical approach is to try to shut down or at least stabilize estrogen with the pill or a GnRH agonist medication like Zoladex.
So. If the conventional medical approach has been to suppress estrogen, does that mean that that’s what we should be trying to do?
The answer is No.
We can try to some extent but estrogen suppression is not easy to do without drugs. In my twenty years of clinical work, I have just never seen that natural modulation of hormones can do much, if anything, for this disease.
Because endometriosis is not like other periods problems. I would argue that it’s NOT a hormonal condition like PMS or PCOS or other women’s health issues.
Endometriosis is affected by hormones, yes, most definitely. But fundamentally endometriosis is something quite different.
It’s an inflammatory disease that I would put in the same category as inflammatory bowel disease and rheumatoid arthritis. As a clinician treating endometriosis, I draw on the treatments that work for those conditions.
So Let’s dive into what is happening with the immune system in endometriosis. Again, the immune system is complex but let’s review a few of the simpler aspects.
The immune system has two main parts. The innate and the adaptive.
The innate immune system consists of macrophages and natural killer cells that should be gobbling up unwanted endometriosis lesions. The innate immune system is also involved in defence against bacteria — which will become important in a few minutes.
The research shows that something is going on with the innate immune system in endometriosis. It’s not doing its job removing endometriosis tissue.
Women with endometriosis have:
- measurably lower natural killer (NK) cell activity in their peritoneal fluid
- reduced phagocytosis by macrophages — even though there are more macrophages present.
So the macrophages are doing LESS gobbling up of the lesions but releasing way MORE pro-inflammatory cytokines and a protein called VEGF which promotes angiogenesis, or the growth of new blood vessels. Which is important for the development of endometriosis.
Macrophages are more likely to release pro-inflammatory cytokines in the presence of gram-negative bacteria, which we’ll come to in a minute. Another teaser.
On the other side of things, we have the adaptive immune system which consists of B and T-cells who respond to antigens and make antibodies. Women with endometriosis have abnormalities there too with more b-cells, t-cells and antibodies.
To say again, women with endometriosis have a different immune environment in their peritoneal cavity compared to women without the disease.
They have less of the gobbling up AND more proinflammatory cytokines and auto-antibodies.
They also have something going with their T-reg cells.
T-reg cells are an interesting group of immune cells that were discovered fairly recently. Their main job is to modulate the adaptive immune system, which means to maintain tolerance to self-antigens and to prevent autoimmune disease.
T-reg cells are generally immunosuppressive. And If you think of the adaptive immune system like an army, the Treg cells are like the generals that keep the soldiers in order.
There’s something going on with T-reg cells and endometriosis it’s not yet 100 percent clear yet what that is. Women with endometriosis have more T-reg cells in the peritoneal cavity but the cells are not doing what they’re supposed to do.
This study out of Japan suggests that at least some of the T-reg cells in endometriosis are not functioning properly. They describe:
A dysregulated immune response wherein the decrease in activated Treg cells exaggerate local inflammation and angiogenesis, and thus facilitates endometriosis progression.
There has been a flurry of other papers and review papers looking into the immune aspect of endometriosis. Here are just a few of them.
The first one — from 2015 — is interesting in that they make the point that at least some of the effects of hormones endometriosis are due NOT to their direct effect on the lesions–but rather… due to the hormones’ indirect effect on the immune system.
For example, progesterone should normally suppress a hyperactive adaptive immune system. But in endometriosis, there is a degree of progesterone-resistance, possibly caused by dioxin exposure, which we’ll talk about a bit later. And so progesterone is not able to rein in the immune system the way it should.
Now, as natural therapists, a dysregulated immune system is something we can help. We have many tools that modulate immune function and reduce inflammation and we can help so many women!
The place to start is of course by modifying the microbiome. I’m sure you’re all aware of the many ways that the microbiome modulates the immune system. For example, the gut microbiome affects endometriosis, as we’ll see.
But there’s also something going on with the pelvic microbiome. Not just the vaginal microbiome, but the uterine microbiome and the pelvic microbiome.
And that “something” could be contamination with gram-negative bacteria.
In this study, they measured the levels of LPS in the menstrual blood and peritoneal fluid of women with and without endometriosis.
LPS is the toxin from gram-negative bacteria such as E coli.
They found that the concentration of LPS endotoxin was four to six times higher in the menstrual blood of women with endometriosis and they state:
..the inflammatory mediator LPS derived from bacterial contamination could be the primary cause in the growth regulation of endometriosis, either alone or in combination with ovarian steroids..”
IF LPS is playing a role in driving endometriosis— I won’t say causing endometriosis — because I doubt it’s that simple. But if it’s driving it, then how is doing that? By upsetting the immune system.
Here you can see that LPS is actually part of the cell wall of gram-negative bacteria. It induces macrophages to release inflammatory cytokines. Which we know that macrophages are doing in endometriosis.
There are ACTUALLY a couple more lines of evidence that bacterial toxins could be a driver of endometriosis:
- Women with a history of a gynecological infection are twice as likely to develop endometriosis.
- Antibiotics can relieve the symptoms of endometriosis.
So, we have E. coli bacteria in the pelvis. How are they getting there?
The paper mentions translocation from the gut lumen to the pelvic cavity. In other words, moving through the intestinal wall into the pelvis. In other words, leaky gut. I recently spoke with a microbiologist who said that endometriosis behaves very much like a microbial disease.
What else do we know?
We know that the combination of LPS plus estradiol is a very strong inducer of the inflammatory cytokines IL6 and TNF-α. That’s the conclusion of this paper where they propose that the combination of LPS plus estrogen as a major driver of endometriosis.
In combination, of course, with other factors. One possible scenario is this:
- The presence of endometriosis lesions.
- PLUS an immune system that is vulnerable to dysfunction either because of genetics or epigenetic changes from toxins (or both).
- PLUS the natural surge in estrogen that occurs with the menstrual cycle.
- PLUS the presence of gram-negative bacteria and LPS toxin.
- PLUS the progesterone resistance that appears to exist with endometriosis. — progesterone should normally have a downregulating effect on both the immune system and the endometriosis lesions
And all of that can lead to the perfect storm that is endometriosis.
So. How can we intervene? Potentially in all of these different factors. The mainstream accepted interventions are:
- remove the lesions
- block estrogen
- give a progestin or potentially high dose progesterone to try to overcome the progesterone resistance
I’m giving a plug to natural progesterone. Also called micronized progesterone.
Real progesterone — so much better— does not have the side effects of progestin drugs. A better choice.
But. As integrative clinicians, we can do more than blocking estrogen and working on progesterone. Way more.
We can also modulate immune function. We can’t change the genetics of a woman’s immune system, obviously. Some people are just born with the haplotype that is prone to endometriosis.
But we can reduce the negative effects of LPS. We can knock back gram-negative bacteria. We can reduce inflammatory cytokines. And we can potentially normalize Treg cells.
Let’s start with knocking back gram-negative bacteria so let’s start with berberine.
Let’s start with berberine-containing herbs which include herbs from Western Herbal medicine, as well as Ayurvedic and TCM. They include goldenseal, Oregon grape, Phellodendron and others. I generally prescribe berberine extract these days.
Berberine has many interesting properties including that is has an antimicrobial effect against gram-negative bacteria and the ability to neutralize the LPS toxin. It also reduces inflammatory cytokines.
Berberine hasn’t been studied for endometriosis but it has undergone one very interesting lab study for adenomyosis, where they concluded that:
“berberine ameliorates the LPS-induced progression of adenomyosis.”
Berberine also potentially repairs intestinal permeability and treats small intestinal bacterial overgrowth (SIBO).
Which brings us to the question. “Does it work by knocking back the gram-negative bacteria in the pelvis or in the gut?”
Because small intestinal bacterial overgrowth is a source of gram-negative bacteria that could then translocate into the pelvis. Which brings us to diet and how that can affect both SIBO and endometriosis.
A 2017 New Zealand clinical trial where they treated IBS sufferers with and without endometriosis. They found that women with endometriosis plus IBS were more likely to respond to a low-FODMAP diet than the women with just IBS.
In other words, there’s something about endometriosis which makes it quite responsive to a diet that removes wheat and dairy and foods that worsen SIBO. The authors speak about visceral hypersensitivity rather than anything to do with inflammation or dysbiosis.
But through my lens, I’m thinking that a low FODMAP diet can potentially reduce inflammation in the gut and knock back gram-negative bacteria and reduce LPS.
The link between LPS toxin in the gut and endometriosis is also discussed in:
This 2016 paper from the American Journal of Obstetrics and Gynecology called “The gut microbiota: a puppet master in the pathogenesis of endometriosis?”
They explore several possible mechanisms by which gut dysbiosis may contribute to endometriosis. Including:
- that LPS promotes inflammation
- that dysbiosis causes dysregulation of the immune system including altered levels of Treg cells and inflammatory cytokines.
- that gut dysbiosis increases the level of circulating estrogen. That would be via beta-glucuronidase made by gram-negative bacteria deconjugating estrogen and pushing it back into circulation.
Beyond a low FODMAP diet… how can diet impact endometriosis?
I find that one of the strongest treatments is to remove antigenic or inflammatory proteins.
Of course, those include gluten and the A1 casein of cow’s dairy.
Both molecules have the potential to disrupt immune function and stimulate the release of inflammatory cytokines.
Both molecules — especially casein — have the potential to stimulate mast cells and histamine.
And finally, both molecules have the potential to increase intestinal permeability, which is going to mean more gram-negative bacteria entering the pelvic cavity.
Unfortunately, we don’t yet have much research to prove or disprove this intervention. There’s one study about gluten that is very encouraging and that I’ve listed here.
But I’m convinced that gluten plays a role. And here’s a bit of homework for you.
It’s a 2014 presentation for the Endometriosis Foundation by reproductive immunologist Jeffrey Braverman. It’s called “outsmarting Endo” and you can find the video and transcript online. In that presentation, Dr. Braverman says something very interesting. He tests all his patients for genetic type or haplotype and finds that many endometriosis-sufferers have the same haplotype as coeliac disease.
And he says that removing gluten can give great improvement.
Beyond gluten, there’s the dairy protein casein. There’s one study that looked at A1 casein inducing gut inflammation.
There’s no test for sensitivity to A1 casein. As a general rule, I ask all endometriosis patients to strictly avoid it. But I do permit them to eat goat and sheep dairy product.
With my patients, I start with gluten and dairy, and then if symptoms don’t start to improve within a couple of cycles, I look for other immune-disrupting agents.
The next immune-disrupting food I consider is eggs which seem to be a factor in about one in three endometriosis patients.
I also consider whether mast cells and histamine is a factor.
Histamine is itself inflammatory but it also leads into a feedforward reaction of too much histamine stimulates the release or estrogen which further increases the release of histamine.
And finally, I consider other toxins especially mold toxins. I’ve had a couple of patients who had bad endo flares after living in a mouldy home.
Of course, there are also all the environmental toxins that disrupt both endocrine and immune function. They include mercury, PCBs, and dioxins.
In this fascinating animal study out of Vanderbilt University, researchers discovered that dioxin exposure in the womb creates resistance of the progesterone receptor that is passed down to future generations. In other words, it’s an epigenetic change that creates a transgenerational risk of endometriosis.
The paper discusses how progesterone normally has a beneficial immunosuppressive effect and how dioxin interferes with that. And they also talk about a double hit on the immune system from bacteria and the LPS toxin. They went so far as to inject dioxin-exposed mice with LPS toxin and then demonstrate a greater risk of endometriosis
So what does that mean for us clinicians? It means we really wish previous generations had not put so much dioxin into the environment because, as you probably know, dioxin doesn’t break down. It’s still circulating in our food supply.
It also means that endometriosis seems to be the result of a combination of genetics and toxin exposure before birth.
In other words, endometriosis is not a lifestyle disease. It’s not something your patients have eaten wrong or done wrong in their lifetime.
And yes, patients can now try to reduce toxin exposure and that might help, but it’s not going to cure the disease.
And I guess, finally, for me, this dioxin study is a cautionary tale about the unforeseen transgenerational effects of environmental toxins. It’s another reason to appeal to our legislators to take action on pollution and environmental toxins. To protect the future generation of daughters from endometriosis and other diseases.
So far, we’ve looked at various ways to modify the microbiome in order to modulate the immune dysfunction that lies at the heart of endometriosis.
Now let’s know look at some additional natural treatments.
The next treatment is zinc. I’m a huge fan of the humble mineral zinc. It’s essential for both healthy hormone and immune function.
This paper outlines various mechanisms by which zinc deficiency plays a key role in endometriosis. Including:
- zinc deficiency causes increased oxidative stress and
- zinc deficiency causes a reduction in the activity of both natural killer cells and Treg cells.
They also make the point that zinc is sequestered during inflammation. In other words, inflammation may cause zinc deficiency rather than the other way around. Hence the title of their image is: zinc deficiency? Cause or consequence.
Another thought is that one of mercury’s toxic effects is to displace zinc in the body.
Next is n-acetylcysteine or NAC, which has undergone one clinical trial in 2013. It was only 95 women but they got good results.
Of the 47 women in the NAC treatment group, 24 cancelled their laparoscopy due to a disappearance of endometriomas, reduction of pain, or pregnancy. The authors go on to say that NAC offers results that are more favorable than those granted by the currently adopted hormonal treatments. And without the side effects.
How does NAC work for endometriosis? Potentially, by several molecular signalling mechanisms.
- NAC downregulates NF-κB.
- NAC is the precursor to glutathione which regulates immune function. Specifically, glutathione upregulates both natural killer cells (the cells who are supposed to be gobbling up the endometriosis lesions) and Treg cells (the cells who are supposed to be preventing overactivity of the adaptive immune system).
- NAC promotes apoptosis and prevents angiogenesis (the growth of blood supply to the endometriosis lesions).
A quick review of the prescriptions so far.
- Possibly a course of antimicrobial berberine
That’s often my frontline prescription for a lot of my patients. Nothing too complicated or mysterious about it. But there are more, of course, including the wonderful turmeric.
Turmeric has been widely investigated for its many anti-inflammatory properties. There are even a couple of curcumin studies specifically for endometriosis.
For example, in this mouse study, they concluded that curcumin treatment regresses endometriosis and has the potential to be an anti-endometriotic drug.
Here are some of its mechanisms of action. Including:
- to dial down a proinflammatory transcription factor called NF-κappa B,
- to promote apoptosis, which is healthy programmed cell death,
- to suppress the local production, similar to how aromatase inhibitors work for the disease. That’s a mouse study of curcumin for endometriosis,
- to inhibit angiogenesis and support the differentiation of naive immune cells into Treg cells (those effects have not yet been investigated specifically for endometriosis).
Let’s look at a couple more.
The next is vitamin A. This was a lab study that found that treatment with retinoic acid or pre-formed vitamin A increases autophagy or programmed cell death in endometriosis tissue. Via a gene called Beclin 1.
It’s a lab study so does not yet support the plan of routinely prescribing vitamin A, but it suggests to me to be on the lookout for vitamin A deficiency. Such as might be indicated by keratosis pilaris – the bumps on the backs of the arms.
Because, remember, that not everyone can efficiently convert plant-derived beta carotene to vitamin A.
Just one more.
Here’s resveratrol, which looks pretty promising according to this 2017 review. The review is based on laboratory and animal studies because there have not yet been any clinical trials.
In this paper, they discuss the mechanisms by which resveratrol may help endometriosis… many of which we’ve seen for some of the other treatments.
The protective effects of resveratrol against endometriosis are mediated through a network of several cell signalling pathways which, in turn, cause suppression of proliferation in endometriotic lesions, induction of apoptosis, reduction of inflammation, angiogenesis and oxidative stress, and inhibition of adhesion and invasion.
Thank you so much for your attention. Here’s a final summary of everything we spoke about today.
- Consider the possible role of bacterial endotoxin (LPS) – and other toxins such as mold and what that does to the immune system.
- Consider a Low-FODMAP diet
- Gluten-free, dairy-free diet
- Vitamin A
I discuss many of these endometriosis treatments in my book Period Repair Manual.