Transcript from my September 2017 presentation at the Endometriosis Symposium in Sydney, Australia.
We’re all here today to try to combat what is a serious, devastating disease. And a disease which I’m happy to see is finally getting some of the attention it deserves both in research and in the popular media.
I think we can agree that endometriosis is complex. It’s not an easy disease to understand or to treat. Today, I want to share with you what I hope are some new useful insights and ideas to help you with your patients. I certainly don’t contend that these are the only effective treatments.
Personally, I’m hopeful that science will soon deliver that lightbulb moment that will bring even better insights and treatment ideas.
In the meantime, there is new research emerging every day and we’ll talk about some of that this morning. There are two 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. Yes, most definitely, estradiol is strongly stimulating to endometriosis and the medical aspect of the conventional approach has been to focus on that and to suppress estrogen with drugs such as the oral contraceptive pill and Synarel or Lupron.
That’s finally shifting a bit with the new, and I would argue—better—treatment with the Mirena IUD which helps endometriosis but does not shut down estrogen.
So, if the conventional medical approach is to suppress estrogen, does that mean that we as natural therapists should be trying to do the same?
Well, we can try to some extent but I would argue that estrogen suppression is not easy to do without drugs. In my 20 years of clinical work, I have just never seen that natural modulation of hormones can do much, if anything, for this disease.
And it seems to me that it’s because endometriosis is not a hormonal condition like PMS or PCOS or the women’s health issues.
Endometriosis is affected by hormones, yes, most definitely. But fundamentally endometriosis is something quite different.
It’s an inflammatory disease and I would invite you to start thinking about it that way.
With my own patients, I don’t put endometriosis in the same category as PCOS or PMS. Instead, I put in the category of other inflammatory diseases like lupus or rheumatoid arthritis I draw on the treatments that work for those conditions.
So Let’s dive into a little of what exactly is happening with the immune system in endometriosis. It’s a huge field of study, but here are 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. It’s fairly well established in the research that the innate immune system is falling down on that job. It’s not removing the endometriosis tissue. For example, women with endometriosis have lower natural killer (NK) cell activity in their peritoneal fluid of women compared with women without endometriosis.
On the other side of things, we have the adaptive immune system which consists of B and T-cells that respond to antigens and make antibodies. Women with endometriosis have a upregulated adaptive immune system in their peritoneal fluid. So they have more b-cells, more antibodies, and more T-cells—except for a certain type of T-cell called a Treg cell which is downregulated in women with endometriosis. We’ll come to that in a minute.
These different aspects of immune function are discussed in a paper called “Immune Interactions in Endometriosis.”
In that paper, they make the very interesting point that at least some of the effects of hormones–of both estrogen and progesterone– on endometriosis are due NOT to their direct effect on the lesions–but rather to their indirect effect on the immune system.
For example, progesterone should normally suppress the 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.
Women with endometriosis have a different immune environment in their peritoneal cavity compared to women without the disease. They have reduced natural killer cell activity. They have more inflammatory cytokines such as TNF-α, IL-6, and IL-8–which is the cytokine that stimulates antibodies. And they have autoantibodies including phospholipid antibodies, lupus anticoagulant, anti-endometrial antibodies.
Finally–and this fairly new information–they have a deficiency of a certain type of T- cells called T-regulatory lymphocytes or Treg cells.
If you think of the adaptive immune system like an army, the Treg cells are like the generals that direct the soldiers to advance or to pull back.
This is an interesting 2017 study from Japan. They found two things:
- Women with endometriosis have fewer Treg cells compared to women without the disease.
- Treg deficiency in mice promotes both the growth of endometriosis lesions and the process of angiogenesis, which is the formation a new blood supply and is a key part of the establishment of the disease. Other diseases associated with low Treg cells and angiogenesis include lupus and rheumatoid arthritis.
These authors concluded that “a dysregulated immune response is a key factor in the etiology of endometriosis.”
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 so let’s look at some of those.
The place to start is, of course, the gut and the microbiome and that brings us to the title of my talk which is: “The microbiome and endometriosis”.
So….. How does the microbiome affect the immune system?
Very directly, as I’m sure you know. For one thing, the gut microbiome modulates the general functioning of the immune system.
With endometriosis, there seems to something a bit more specific going with the immune system of the peritoneal fluid and the microbiome of the reproductive tract.
What do we know?
We know that infection or disruption of the vaginal microbiome seems to promote the development of endometriosis. That’s the first study here. They found that women a history of a pelvic infection are twice as likely to develop endometriosis.
The second paper is a 2017 study that found that infection is more common in women with endometriosis and that furthermore, treatment with antibiotics can alleviate symptoms of endometriosis.
Which is intriguing. But does that mean that infection directly causes endometriosis?
No. Not necessarily. Endometriosis is a complex disease.
BUT the correlation with bacteria could be– at least in part– because of a bacterial toxin called lipopolysaccharide or LPS and the way it upsets the immune system.
LPS is actually part of the wall of gram-negative bacteria such as E coli. And it reacts very strongly with the immune system. LPS is a known inducer of immune dysfunction and inflammation.
And here are two more things that we know:
- Women with endometriosis have more gram-negative bacteria in their endometrium compared to women without the disease.
- The combination of LPS plus estradiol is a very strong inducer of the inflammatory cytokines IL6 and TNF-α. The authors of this paper propose that that combination may play a role in the development of endometriosis.
In combination, of course, with other factors.
One possible scenario is this.
- Take a woman who already has the lesions present, possibly from retrograde menstruation… or possibly laid down at birth, or deposited there by the lymphatic system
- And then add a certain type of immune system that is vulnerable to dysfunction because of either genetics or environmental toxins… or both.
- And then add the natural surge in estradiol that occurs with the onset of menstruation.
- And then add the presence of too many gram-negative bacteria and lipopolysaccharide.
- And then add the progesterone resistance that appears to exist with endometriosis. As I mentioned, progesterone should normally have a downregulating effect on both the immune system and the endometriosis lesions
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
- And give a progestin or potentially high dose progesterone to try to overcome the progesterone resistance
And I agree with that approach.
But we can do 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 work to normalize–as much as possible– immune function. That includes reducing the negative effects of LPS, reducing inflammatory cytokines, and supporting Treg cells. We have the tools to do this. So let’s take a look.
First, we have tools to modify both the gut and the uterine microbiome.
This 2016 paper from the American Journal of Obstetrics and Gynecology is 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. The strongest is that dysbiosis causes dysregulation of the immune system including altered levels of Treg cells and inflammatory cytokines.
They also mention LPS and its role in promoting inflammation.
And finally, they make the point that gut dysbiosis increases the level of circulating estrogen.
We know that dysbiosis can promote inflammatory disease. And we know that treating dysbiosis can relieve the symptoms of endometriosis.
This 2017 New Zealand clinical trial found that endometriosis improves on a low-FODMAP diet. The authors do not go so far as to say that dysbiosis causes endometriosis, but only that IBS and endometriosis are strongly correlated and that the diet can bring relief to both.
With my own endometriosis patients, I often start with something like a low-FODMAP diet but only after I’ve first assessed for SIBO or small intestinal bacterial overgrowth. If they do have SIBO, then I prescribe a short-term low-FODMAP diet together with a herbal antimicrobial such as berberine, which we’ll discuss in a few minutes.
I don’t like a low FODMAP long-term because it does not address the underlying bacterial overgrowth.
Beyond a low FODMAP diet, how can diet impact endometriosis?
One of the strongest treatments is to remove antigenic or inflammatory proteins from the diet. Of course, those include gluten and the A1 casein of cow’s dairy. Both molecules disrupt immune function and stimulate the release of inflammatory cytokines.
Unfortunately, we don’t yet have much research to prove or disprove this intervention. We do have 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 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. As far as I know, there are no studies looking at a casein-free diet and endometriosis. But there are studies showing that A1 casein generates inflammation in the gut.
What do I mean by A1 casein? I mean the casein variant from Friesian cows. It’s potentially highly inflammatory in some people in much the same way as gluten. A1 casein is different from the A2 casein found in the dairy from goats, sheep, and some types of cow.
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. A clinical sign that can confirm a casein sensitivity is a history of recurrent upper respiratory infections in childhood. Either ear infections, bronchitis or tonsillitis. That immune disruption by A1 casein can worsen those childhood conditions, but then in adulthood, I find that the same immune disruption can drive other inflammatory conditions such as endometriosis.
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. And just to clarify, I think eggs are a great food—a healthy food in general. They’re a good source of protein and iron and I’m not worried about the cholesterol. I’m just saying that eggs are a common food sensitivity and can potentially disrupt immune function in some women. I have seen some endo patients improve off eggs. There’s no one-size-fits-all endometriosis diet.
I also consider whether histamine intolerance is a factor. Histamine is itself inflammatory but it also leads to a feedforward reaction of too much histamine stimulates the release or estrogen which further increases the release of histamine. I discuss histamine intolerance quite a lot in my new book.
And finally, I consider other toxins especially mold toxins. I recently had a patient who had a bad flare during two years that she lived in a moldy unit. She did improve somewhat when she left that place, but by then the endometriosis was quite bad and we weren’t able to calm it with natural treatment alone. And she had to have another surgery.
Of course, there are also all the environmental toxins such as mercury, dioxins, and PCBs that disrupt both endocrine and immune function.
A word here about the role of environmental toxins—particularly the role of dioxins.
In a fascinating animal study out of Vanderbilt University, researchers discovered that dioxin exposure in the womb creates a resistance of the progesterone receptor that is passed down to future generations. Hence, creating 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 with bacteria and 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, particularly in animal products.
It also means that endometriosis does seem 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.
And yes, they 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.
Now let’s look at some of the key supplements and herbal medicines which I find are the best. This is by no means an exhaustive list of medicines but it’s some of the big ones.
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.
Berberine has many interesting properties including most prominently an antimicrobial effect against gram-negative bacteria. And berberine has been shown to neutralize LPS toxin and reduce inflammatory cytokines.
Berberine can also directly improve the gut microbiome and treat bacterial overgrowth. The 2014 John Hopkins study that found that a berberine-containing herbal medicine was as effective for as antibiotics for small intestinal bacterial overgrowth.
With my own patients, I do give berberine—but not usually as an ongoing treatment because I am concerned it might deplete gut bacteria. So, instead, I prescribe an 8-week course of either goldenseal or Metagenics Bactrex. If it gets good results, I might repeat the 8-week course again after a break of a month or two.
There’s potentially a role for other antimicrobial treatments and gut treatments including oregano, wormwood, and others.
And following berberine, I will usually give a probiotic but I haven’t yet settled on the best one. I would really love to be guided by the research on this one and hopefully, we’ll see some new endometriosis-specific probiotics in the near future.
For example, a strain of Lactobacillus gasserei did well in a double-blind, placebo-controlled clinical trial for endometriosis. The researchers say upregulates natural killer cells, and reduces angiogenesis.
At this stage, we I don’t think we can access this strain clinically. With my own patients, I am currently using products like Bioceuticals Zonuguard and Metagenics Ultra Flora Immune control that contains strains that have been trialed for inflammatory disease.
I predict we’ll see endometriosis-specific probiotics in the future—hopefully.
So far, we’ve looked at various ways to modify the gut microbiome in order to modulate the immune dysfunction that lies at the core of endometriosis. And just to summarise, those interventions include addressing SIBO or small intestinal bacterial overgrowth, as well as removing antigenic foods, and giving antimicrobial herbs to reduce endotoxin, and finally probiotics to modulate immune function.
Now let’s know look at some additional natural treatments that work via the gut but also have direct effects on the immune system and endometriosis.
Next is selenium, which has been demonstrated to be deficient in endometriosis sufferers. Selenium has powerful anti-inflammatory and immune-modulating properties and has been shown to upregulate Treg cells in other types of inflammatory disease.
Selenium also helps to support the formation of the corpus luteum and therefore the formation of progesterone, which should have a further beneficial effect. And to tie it back to the gut, a problem in the gut—such as SIBO or bacterial overgrowth—can deplete the body of selenium.
The next treatment to think about is zinc. I’m a huge fan of the humble mineral zinc. It’s essential for both healthy hormonal and immune function. This Italian study found that women with endometriosis have lower levels of serum zinc compared to women without the disease. And they go on to propose that zinc deficiency plays a key role in the etiology of the disease. They outline various changes that occur with zinc deficiency including an increase in oxidative stress as well as a reduction in the activity of natural killer cells and a decrease in Treg cells. They also make the point that zinc is sequestered during inflammation. In other words, that the inflammation may come first and cause zinc. Which is why the title of their image is: zinc deficiency? Cause or consequence.
Another interesting thing to think about here is that one of the biggest effects of environmental toxins such as mercury is to displace zinc in the body.
I prescribe a lot of zinc to my endometriosis patients and I find it’s helpful. Sometimes, I test first with plasma zinc but I don’t rely on that. I look more to medical history. For example, if an endometriosis patient is vegetarian or on the Pill, then she needs zinc.
Now we come to the wonderful turmeric.
Turmeric has, of course, been widely investigated for its many anti-inflammatory properties. There are even a couple of studies specifically for endometriosis. Here’s one of them in which they got some pretty dramatic results. It was not a clinical trial but was rather a mouse study, and they found that curcumin treatment regresses endometriosis and should be considered as a drug.
They said that curcumin’s mechanism of action was by dialing down a proinflammatory transcription factor called NF-κappa B, and also by accelerating apoptosis, which is healthy programmed cell death.
Another laboratory study found that curcumin inhibits endometriosis cells by suppressing their production of estrogen, similar to how aromatase inhibitors work for the disease. Turmeric also inhibits angiogenesis and supports the differentiation of naive immune cells into Treg cells—but those effects have not yet been investigated specifically for endometriosis.
Truly, I think turmeric is a potentially very powerful medicine for endometriosis and it’s great because it’s safe for long-term use.
My front line treatments are casein-free, gluten-free. zinc. Selenium and turmeric. Nothing too complicated or mysterious about this. They’re anti-inflammatory. Immune-modulating. And they get results.
Let’s look at a couple more.
There’s N-acetyl cysteine, which has undergone a small clinical trial in Italy. It was a preliminary trial of only 95 women but the authors were very enthusiastic about their results. Of the 47 women in the NAC treatment group, 24 canceled 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 signaling mechanisms. Like turmeric, it downregulates NF-κabba B. It is also the precursor to glutathione which, as you probably know, is a profound immune regulator. Specifically, glutathione upregulates both natural killer cells–the ones who are supposed to be gobbling up the lesions—and also Treg cells, who are the ones supposed to be calming down all the cytokines and autoantibodies.
NAC has many other potential benefits including the promotion of apoptosis and the prevention of angiogenesis.
Finally, we come to resveratrol, which I haven’t actually prescribed a lot myself, but which looks pretty promising according to this new 2017 review. There have not yet been any clinical trials of the phytonutrient. The review is based on laboratory and animal studies. 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 signaling 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.”
This is an image from the actual paper where they compiled all of the many ways that resveratrol acts on molecular signaling pathways. You see inflammatory cytokines and also the important the inducer of inflammation NF-kappa b which plays a role in proliferation, apoptosis, and inflammation.
Thanks for your attention everyone. Here’s a summary of everything we spoke about today.
- The possible role of LPS toxin
- Berberine—mainly because it suppresses LPS toxin
- Gluten-free, dairy-free
- Low-FODMAP diet
- Zinc and selenium
I discuss many of these in my new book Period Repair Manual. It’s available on Amazon, iTunes, etc.