Inflammation, immunity & your microbiome ~ a holistic view of endometriosis
Just what is ‘endo’?
Endometriosis (endo) is a complex chronic gynaecological disease, where tissue similar to the endometrial lining of the uterus, is found elsewhere:
Ovarian endometriosis - where endometrial lesions grows on the ovaries (also called an endometrioma or chocolate cyst)
Deep infiltrating endometriosis - where endometrial tissue grows on the bladder, bowel, uterine ligaments
Peritoneal endometriosis - the peritoneum is a thin layer of membrane (like cling wrap) lining the pelvic cavity and covering its organs. Superficial endometriosis can grow here.
(Adenomyosis is where endometrial tissue grows inside the uterine muscle wall, and some would call this a fourth type of endometriosis)
You can see here the four forms of endometriosis: 1. Ovarian endometrioma (OMA) 2. Superficial peritoneal endometriosis (SUP) 3. Deep infiltrating endometriosis (DIE) 4. Adenomyoma (Ad). Image from Chantalat E et al. Estrogen receptors and endometriosis, Int J Mol Sci, 2020, 21(8):2815
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Endometriosis is estimated to affect up to 10% of women (20-30% of women with sub-fertility), with symptoms such as period pain, pelvic pain, back pain, ovulation pain, pain during intercourse, pain during urination, pain passing a bowel movement, bowel irregularities, heavy bleeding and sub-fertility.
Yes, you read that right - pain, pain, pain, pain, pain, pain…
This seriously affects not only a woman's physical health, but her mental health, her social and sexual relationships, and her financial wellness (due to regular professional absenteeism)...you know, just her entire quality of life!
And yet endometriosis is still not fully understood, and is a slippery disease. The severity of symptoms doesn't always correlate with the severity, or even presence, of the disease, and asymptomatic women can be diagnosed with endometriosis.
Endometriosis as a hormonal disease
Like the endometrial tissue lining the uterus, endometriosis lesions are hormonally active and responsive tissues. They respond to circulating oestrogen and can actually synthesise oestrogen as well. They build up and bleed just like the endometrium inside our uterus, only the lesions are bleeding into our pelvic space. All this leads to the host of symptoms experienced by women with endo.
Endometriosis has always been thought of as a hormonal disease. An oestrogen-dependant condition. And it is, in part. That's why hormonal suppression works so well for some women eg. the Pill, progestins such as the Mirena IUD, or a GnRH agonist like Zoladex. The aim with these medications is to suppress ovulation, or thin and reduce the endometrium & endometrial lesions. Note though, these medications aren't without their own side effects that some women find equally as challenging as their endometriosis - it's a balancing act!
But research is discovering that endometriosis is So Much More than a hormonal condition.
It could all be down to inflammation
The long-standing thought about just how women get endometriosis, is that it's due to retrograde menstruation (there are a few theories though). This is where menstrual blood (and endometrial tissue) flows 'backwards' up through the fallopian tubes and out into the pelvic cavity, at menstruation. Retrograde menstruation probably occurs in most women though..so why do some women go on to develop endo, but the rest don't.
Inflammation?
You see, those retrograde endometrial cells need to stick to something (an ovary, the bladder etc) to become an endometrial lesion. An inflammatory pelvic environment enhances the 'stickiness' of endometrial cells.
Women with endometriosis seem to have
greater numbers of inflammatory chemical messengers (cytokines) than other women
↓
Higher levels of inflammatory cytokines,
coupled with the inflammatory environment created by a predominance of oestrogen
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Stimulate those rogue endometrial cells
to attach, develop a blood supply, and establish endometriosis lesions
It's also thought the higher degree of inflammatory cells seen in endometriosis might negatively affect maturing eggs and implantation, thus impacting fertility.
Endometriosis is a disease of inflammation
Endometriosis and your immune system
The chronic low-grade inflammation present in endometriosis has another effect - it activates greater immune cell activity and dysregulation. Hmm, or maybe the immune dysregulation feeds the inflammation! It's a chicken and egg scenario! Either way, immune system differences are found between women with and without endo, and there are localised abnormalities in every type of immune cell in women with endometriosis.
Immune dysregulation contributes to inflammation, and a reduces the immune system’s ability to:
efficiently detect cellular abnormalities like rogue endometrial cells and
to 'clean up' debris
as well as an increased likelihood of:
adhesion of endometrial tissue and
scar formation
leading to disease progression.
Some of our immune cells (our mast cells) might also play a role in the pain of endometriosis, and our sensitivity to it, by having a direct effect on nerve endings.
There's also the question of auto-immunity being involved in endometriosis. Auto-immunity is where our immune system mistakenly 'attacks' self, and a range of auto-immune antibodies are often found in women with endo (ANA, Anti-DNA antibodies, anti-phospholipid antibodies).
It's not yet known what the relationship is between autoimmune disease and endo.
Is one the consequence of the other?
Do they share similar underlying mechanisms?
IS endo an outright autoimmune disease?
What is known is that having endometriosis puts you at higher risk of having another auto-immune disease, such as SLE, Sjogren’s syndrome, Rheumatoid arthritis, Coeliac disease, MS, or Inflammatory bowel disease.
Endometriosis is a disease of immune dysregulation
Endometriosis and your microbiome
Our gut flora plays a role in oestrogen metabolism and also immune cell development and composition. Disordered gut flora (dysbiosis) might influence endometriosis development and progression via these mechanisms.
But we also find ourselves with another chicken and egg scenario, because studies have shown that when endometriosis is surgically induced in animals, a distinct (dysbiotic) gut microbiota develops - endometrial lesions themselves can alter gut flora!
So was the dysbiosis there first, or did the endo create it?
Supporting the idea that gut flora might influence endo, a small pilot study showed that women with endometriosis, when given a specific Lactobaccillus-dominant probiotic + prebiotic to take orally, experienced a decrease in pain levels compared to women given placebo treatment, most noticeable after a 8 - 12 week period.
And what about the microbiome of our uterus? Or vagina? Could they also play a role in the development or progression of endo?
Women with a history of pelvic inflammatory disease (PID) are three times more likely to develop endometriosis. PID involves an infection travelling from the vagina up into the uterus, fallopian tubes and ovaries, so for some women there may be a bacterial component to their endo.
Researchers found differences in the vaginal, cervical and gut microbiota of women with endometriosis compared to a control group. The women with endo had greater numbers of pathogenic bacteria Gardnerella, Streptococcus, Escherichia, Shigella and Ureaplasma at the cervix than controls, as well as differences in their gut flora (Shigella and Escherichia dominant). Dysbiosis has also been identified in the pelvic peritoneal fluid and menstrual fluid, of women with endo . These problematic bacteria secrete a toxin called LPS (liposaccharide) that itself increases inflammation.
This diagram shows all the ways a healthy microbiome vs a dysbiotic one, could influence the development and progression of endometriosis.
(A). A healthy microbiota regulates factors involved in maintaining normal peritoneal environment and endometrial cell clearance. (B). Dysbiosis contributes to the dysregulation of factors driving endometriosis onset and progression. Image from Jiang I et al, Intricate Connections between the Microbiota and Endometriosis. Int J Mol Sci. 2021;22(11):5644
Endometrioisis is a disease of dysbiosis
I think I have endo - what next?
It's important to get diagnosis and treatment to reduce the chances of scarring and adhesions occurring. Especially if you have a history of 'unexplained' infertility or unsuccessful IVF cycles.
If you suspect you have endometriosis, but your GP is dismissive - 🚩 🚩 🚩 - do seek a second opinion. Unbelievably, it takes women on average up to 10 years before a diagnosis. This is too long to live with uncomfortable symptoms.
A laparoscopy is considered gold-standard for diagnosis (to identify if endometriosis is present) and treatment (for the surgical removal of lesions), but surgery is obviously an invasive and expensive first line intervention. Access to laparoscopic surgery is also, sadly, not equally available to all women across the country.
Other less-invasive, exploratory options for an initial diagnosis are:
CA-125 blood test
A blood marker for gynaecological cancers that is mildly elevated in endometriosis. It's a good place to start to see if further investigations are warranted.
DIE ultrasound
A regular trans-vaginal ultrasound is not sufficient to detect endometriosis. A DIE is a specific ultrasound looking for deep infiltrating endometriosis. It involves a bit of bowel prep beforehand in order to empty the bowel for a better chance to visualise any lesions (yep! Laxatives the night before and an enema just prior!)
If you have an elevated CA-125, and potential lesions or scarring were picked up in the DIE scan, your GP/gynaecologist/fertility specialist will likely refer you on for a laparoscopy, and the excision of any endometrial lesions. Excision surgery is The Best Way to remove endometriosis.
But...excision is not a cure - 40% of women will experience the recurrence of lesions within 5 years. The mechanisms at play that caused the endometriosis in the first place are still there. So ongoing management should be a consideration, especially if you're symptomatic.
Also, excision doesn't work for everyone.
Women with low ovarian reserve and endometriosis on their ovaries (endometrioma's) may look at surgery as a last resort, as removing endometriosis from the ovaries can also remove precious eggs
For women with superficial peritoneal endo, or nerve pain, surgery might actually make their symptoms worse
So, if surgery is currently the best-known treatment there is, but it's not for everyone, then more research should absolutely be undertaken into other treatment and management interventions - including diet and naturopathy.
Endometriosis and your diet
An Australian study showed that 44% of women with endometriosis use dietary interventions to manage their endo (eg. gluten-free, vegan, low-FODMAP) and experienced a 64% reduction in pain. That's pretty impactful!
Vegies
Studies have shown that women with a higher daily intake of vegetables, particularly green vegetables, had the greatest reduction of risk for endometriosis. In addition, one cup a day of cruciferous veg like cabbage, broccoli, brussels sprouts and cauliflower, may also be protective (these veg assist with oestrogen metabolism). Plus the fibre in veg will increase Sex Hormone Binding globulin (SHBG), thus decreasing oestrogen.
Red meat
There's mixed research around endometriosis and red meat intake, with some studies showing no correlation, and others pointing to an increased risk seen with the highest intake of red meat (2+ serves/day vs less than 1 serve/week). Meat is considered inflammatory (due to its stimulation of inflammatory prostaglandins), and also decreases SHBG, which in turn will increase oestrogen. I suggest limiting its intake in endo.
Dairy
Research is inconclusive around dairy and endometriosis. One small pilot study demonstrated higher rates of bowel disturbance and inflammation in subjects drinking regular cow's milk vs A2 milk. In practice I see an improvement in period pain in those women that avoid cow's dairy. If you decide to give this a try, remove cow's dairy for a full menstrual cycle to see if you notice any change. Then have a 'challenge' blow-out (ice cream! cheese board!) and see if you notice any rebound bowel changes (bloating, loose stools), endo symptoms, or upper respiratory mucus production - a sure sign that dairy isn't your best friend.
Gluten
Endometriosis is associated with having the HLA-DQ2 and DQ8 genes that are also present in patients with Celiac disease. When gluten binds to these receptors an inflammatory immune response is triggered, contributing the experience of chronic pain.
An Italian study of over 200 women with either period pain, pelvic pain or pain with intercourse, went on a gluten free diet for 12 months (in Italy! Omg!). Pain symptoms were assessed before and after, and 75% of participants reported improved symptoms after following a gluten-free diet for 12 months! I see this sort of result mirrored in clinic as well. If you give this a try, remove gluten for at least two months to see how symptoms improve. Then have a 'challenge' meal (pasta! pizza! bread!) to see if you experience any rebound symptoms.
What about Naturopathy?
When commencing treatment for endometriosis, I always emphasise there is no cure for endo - we are working together in a management role
I also like to get really specific about your experience of endometriosis, your full symptom picture (pain, periods, bowels, endo-belly etc), in order for us to monitor progress. Our progress won't be instant, but I would usually expect to see a 50% reduction in pain over 6 months.
Treatment will be with dietary changes (as above, and often involving eliminating dairy and gluten for a time) and lifestyle changes (particularly minimising environmental exposures to endocrine-disrupting chemicals).
And then I pull out the ✨ Big Magic ✨ ...herbal and nutritional medicine.
With herbal and nutritional medicine I can tailor a prescription specifically for you and your experience of endo. I will always focus on anti-inflammatory activity, immune system modulation, gut and microbiome support and oestrogen metabolism, but I can also directly focus on how your endo impacts you in particular.
Herbal and nutritional medicine can target period pain, pelvic pain, back or leg pain, heavy periods, fatigue, constipation, diarrhoea, bloating, stress, anxiety, depression and urinary issues. It can be highly individualised, because I can guarantee, your experience is going to be different to the next person I talk to.
Treatment might be in the form of liquid or tableted herbs, nutritional powders or capsules, or herbal teas. Sometimes I'll refer you to other supportive modalities, like pelvic floor physiotherapy, counselling, or maya abdominal massage.
I will always be on your cheer squad, and that's important medicine too!
Resources
If you have any questions for Jacintha about endometriosis or your fertility, please make an appointment to discuss with her.
You might also be interested in:
a meal planning template to assist in your dietary changes for your endo
this article about endocrine disruptors
this article about food for fertility
Additional references
Afrin S, AlAshqar A, El Sabeh M, Miyashita-Ishiwata M, Reschke L, Brennan JT, Fader A, Borahay MA. Diet and Nutrition in Gynecological Disorders: A Focus on Clinical Studies. Nutrients. 2021; 13(6):1747. https://doi.org/10.3390/nu13061747
Agostinis, Chiara et al. “Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target.” Frontiers in immunology vol. 11 599117. 11 Jan. 2021, doi:10.3389/fimmu.2020.599117
Armour, Mike et al. “Self-management strategies amongst Australian women with endometriosis: a national online survey.” BMC complementary and alternative medicine vol. 19,1 17. 15 Jan. 2019, doi:10.1186/s12906-019-2431-x
Chantalat E, Valera MC, Vaysse C, et al. Estrogen Receptors and Endometriosis. Int J Mol Sci. 2020;21(8):2815. Published 2020 Apr 17. doi:10.3390/ijms21082815
Della Corte L, Di Filippo C, Gabrielli O, Reppuccia S, La Rosa VL, Ragusa R, Fichera M, Commodari E, Bifulco G, Giampaolino P. The Burden of Endometriosis on Women's Lifespan: A Narrative Overview on Quality of Life and Psychosocial Wellbeing. Int J Environ Res Public Health. 2020 Jun 29;17(13):4683. doi: 10.3390/ijerph17134683. PMID: 32610665; PMCID: PMC7370081
Ho, S, Woodford, K, Kukuljan, S, Pal, S, Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: A blinded randomised cross-over pilot study, European Journal of Clinical Nutrition, 2014, 68(9)
Jiang I, Yong PJ, Allaire C, Bedaiwy MA. Intricate Connections between the Microbiota and Endometriosis. Int J Mol Sci. 2021;22(11):5644. Published 2021 May 26. doi:10.3390/ijms22115644
Khan KN, Fujishita A, Hiraki K, Kitajima M, Nakashima M, Fushiki S, Kitawaki J. Bacterial contamination hypothesis: a new concept in endometriosis. Reprod Med Biol. 2018 Jan 18;17(2):125-133. doi: 10.1002/rmb2.12083. PMID: 29692669; PMCID: PMC5902457
Khodaverdi, S., Mohammadbeigi, R., Khaledi, M., Mesdaghinia, L., Sharifzadeh, F., Nasiripour, S., & Gorginzadeh, M. (2019). Beneficial Effects of Oral Lactobacillus on Pain Severity in Women Suffering from Endometriosis: A Pilot Placebo-Controlled Randomized Clinical Trial. International journal of fertility & sterility, 13(3), 178–183. https://doi.org/10.22074/ijfs.2019.5584
Marziali, M, Venza, M, Lazzaro, S, Lazzaro A, Micossi, C, Stolfi, M, Gluten-free diet: a new strategy for management of painful endometriosis related symptoms? Minerva Chir 2012(67)499-504
Osborne-Crowley, L, 'A common treatment for endometriosis could actually be making things worse’, The Guardian Australia, 2021 July 2
Shigesi N, Kvaskoff M, Kirtley S, Feng Q, Fang H, Knight JC, Missmer SA, Rahmioglu N, Zondervan KT, Becker CM. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Hum Reprod Update. 2019 Jul 1;25(4):486-503. doi: 10.1093/humupd/dmz014. PMID: 31260048; PMCID: PMC6601386
Yamamoto, Ayae et al. “A prospective cohort study of meat and fish consumption and endometriosis risk.” American journal of obstetrics and gynecology vol. 219,2 (2018): 178.e1-178.e10. doi:10.1016/j.ajog.2018.05.034
