Endometriosis : new findings shed light on the cause

Endo­me­trio­sis is a bur­den for a sub­stan­tial num­ber of women and those assi­gned female at birth (AFAB). This inflam­ma­to­ry disease, which touches about 1 in 10 women of repro­duc­tive age glo­bal­ly¹, can cause debi­li­ta­ting chro­nic pain and poor fer­ti­li­ty and was recent­ly found to be lin­ked to a whole host of comor­bi­di­ties. It has been his­to­ri­cal­ly under-resear­ched, but recent advances are giving the field hope. We take a look at what resear­chers are exci­ted about.

Kri­na Zon­der­van. What we’re seeing now is the result of a gra­dual increase in awa­re­ness over time. When I star­ted wor­king on endo­me­trio­sis as a student in the mid-1990s, most people wouldn’t real­ly have heard of it, be it men or women. I’ve seen that qui­ck­ly change over the past decades.

It’s not just endo­me­trio­sis, it’s women’s health as a whole that has been emer­ging from the fringes of research. Within the annals of bio­me­di­cal research in gene­ral, females and AFAB people have long been trea­ted as “small men”, with doses of medi­cines deve­lo­ped using males sim­ply adjus­ted for weight and sta­ture.  That clear­ly dis­re­gards how the com­plex hor­mo­nal sys­tems inter­act with biology.

There’s now a much wider ack­now­led­ge­ment that this dearth of research is a huge bur­den on socie­ty. The World Eco­no­mic Forum publi­shed a report² in Janua­ry with McKin­sey esti­ma­ting that clo­sing the women’s health gap could save the glo­bal eco­no­my about $1 tril­lion annual­ly. It’s just stag­ge­ring — I think this real­ly made people sit up. This has been accom­pa­nied by coun­tries put­ting women’s health as an impor­tant agen­da item for research.

In the US, for ins­tance, First Lady Jill Biden laun­ched a White House Ini­tia­tive³ this past Februa­ry put­ting 100 mil­lion dol­lars into tack­ling key aspects of women’s health that haven’t real­ly been addres­sed appro­pria­te­ly so far. The Women’s Health Stra­te­gy for England, publi­shed in 2022, as well as the Women’s Health Plan for Scot­land in 2021 have gene­ra­ted a fan­tas­tic and much nee­ded focus on impro­ving women’s health mana­ge­ment. France has also clear­ly empha­si­sed impro­ving things for women with endometriosis.

I think it’s rea­so­na­bly well accep­ted that super­fi­cial per­ito­neal disease, that can occur around the inside of the abdo­men, comes from what we call retro­grade mens­trua­tion. Almost all women and AFAB people will have some mens­trual blood flo­wing back up the fal­lo­pian tubes and into the pel­vic cavi­ty. Some of that mens­trual debris contains viable endo­me­trial cells and these are most like­ly what causes the per­ito­neal lesions.

This idea is sup­por­ted by many stu­dies. Lab stu­dies found that endo­me­trial cells see­ded in mouse models deve­lo­ped these lesions. Epi­de­mio­lo­gi­cal stu­dies sho­wed a link bet­ween endo­me­trio­sis risk and ear­lier age when per­iods start, shor­ter cycles as well as hea­vier mens­trual blee­ding⁴. Gene­tic stu­dies buil­ding on the work of Lui­za Moore publi­shed in Nature in 2020⁵ sho­wed that muta­tions ari­sing natu­ral­ly in the endo­me­trium could be found in these per­ito­neal lesions. These all indi­cate a clear link with the ori­gin of these lesions.

The ques­tion now is why these lesions only deve­lop in some women and AFAB people. Are there dif­fe­rences in, say, the immune sys­tem or in the hor­mo­nal sys­tem ? Are other fac­tors invol­ved ? That’s what research into causes is pri­ma­ri­ly focu­sed on.

Yes, it’s real­ly dif­fi­cult to fol­low the pro­gres­sion of disease, espe­cial­ly super­fi­cial lesions. Cer­tain sub­types such as ova­rian endo­me­trio­sis (cysts on the ova­ries) or deep nodu­lar disease, you can usual­ly visua­lise through ima­ging, but with super­fi­cial endo­me­trio­sis, the only way to see how the disease might be evol­ving is through surgery.

We also don’t have many spon­ta­neous models of the disease — out­side of humans, very few ani­mals mens­truate and have meno­pause. There are some non-human pri­mates, such as rhe­sus macaques, that can deve­lop endo­me­trio­sis spon­ta­neous­ly like humans. But of course, that’s a very dif­fi­cult spe­cies to stu­dy. There are some lab models avai­lable, the clo­sest to human phy­sio­lo­gy being the mens­trua­ting mouse model⁶ deve­lo­ped by Erin Greaves that com­bines see­ding endo­me­trial tis­sues with an indu­ced hor­mo­nal fluc­tua­tion pat­tern to pro­mote these lesions to grow. But none of these tru­ly reflect the human situation.

A poten­tial exci­ting way for­ward under deve­lop­ment are orga­noids — dif­ferent human cell types grown toge­ther in the lab that reflect the more com­plex archi­tec­ture of human tis­sues for research. This work is still in its infan­cy as the endo­me­trium is a very com­plex tis­sue, but I believe we will see some mas­sive impro­ve­ments on that front in the coming years.

We’ve known for a long time that endo­me­trio­sis can run in fami­lies — about 50% of disease risk⁷ in the gene­ral popu­la­tion is attri­bu­table to gene­tic fac­tors, which is a sizable heri­ta­bi­li­ty. But endo­me­trio­sis is what we term a com­plex disease, which means that gene­tic fac­tors and envi­ron­men­tal fac­tors and other aspects we don’t quite unders­tand yet all contri­bute to risk. No single gene would explain the majo­ri­ty of fami­lial cases. Still, our work⁸, a high­ly col­la­bo­ra­tive ana­ly­sis of glo­bal gene­tic data­bases pro­vides some clues. We found about 40 regions of the genome that har­bour variants known to increase the risk of endo­me­trio­sis. These variants could be lin­ked to par­ti­cu­lar path­ways, which is ope­ning up new lines of research.

Endo­me­trio­sis is a « com­plex » disease, which means that gene­tic fac­tors and envi­ron­men­tal fac­tors and other aspects we don’t quite unders­tand yet all contri­bute to risk.

Through this work, we also dis­co­ve­red a sha­red gene­tic basis for a whole host of co-mor­bi­di­ties for the disease. Some of these were per­haps obvious, for ins­tance sha­red risk with other repro­duc­tive condi­tions such as ute­rine fibroids. These pre­su­ma­bly share hor­mo­nal risk fac­tors with endo­me­trio­sis that are gene­ti­cal­ly regu­la­ted. But some of the other condi­tions we found to be lin­ked with endo­me­trio­sis, such as inflam­ma­to­ry condi­tions like asth­ma and osteoar­thri­tis, and pain condi­tions like low back pain, migraine, and mul­ti­site pain, came as quite a sur­prise. It could mean exis­ting treat­ments for these condi­tions could be repur­po­sed for endo­me­trio­sis and vice ver­sa, or new treat­ments could be deve­lo­ped across these.

The­re’s a rea­li­sa­tion, which I think is a real­ly heal­thy one, that sur­ge­ry will not neces­sa­ri­ly bene­fit eve­ryone. This is par­ti­cu­lar­ly true for those who have had mul­tiple sur­ge­ries and either their disease has come back or their symp­toms have not resol­ved after the inter­ven­tion, or those who are very young. The mains­tay of treat­ment still tends to be hor­mo­nal treat­ments of various dif­ferent guises. First-line treat­ment is an oral contra­cep­tive, which can work effec­ti­ve­ly in some women, but can’t be used if the per­son wants to conceive. In the same line, there are Gona­do­tro­pin Relea­sing Hor­mone (GnRH) ana­logues, treat­ments that effec­ti­ve­ly shut down the hor­mo­nal axis and create a form of medi­cal meno­pause. These come as both ago­nists and anta­go­nists — there are pros and cons to both.

Having those options is good, but the real need lies in the deve­lop­ment of non-hor­mo­nal treat­ments. That’s ulti­ma­te­ly what women want, and both aca­de­mia and various com­pa­nies are loo­king into deve­lo­ping these.There’s inter­est, for ins­tance, in immu­no­lo­gi­cal treat­ments dam­pe­ning the inflam­ma­tion asso­cia­ted with endo­me­trio­sis. That’s a tri­cky one, of course, because like any­thing invol­ving the immune sys­tem, such treat­ments could trig­ger side effects.

Pret­ty much all the cli­nics in the UK that treat endo­me­trio­sis see indi­vi­duals who iden­ti­fy as women and trans men. All the concerns we have about how to manage the disease and how to treat it clear­ly affect both groups equal­ly, although trans men are an under-stu­died group in terms of opti­mal disease mana­ge­ment. Inclu­si­vi­ty in both opti­mi­sing cli­ni­cal mana­ge­ment, addres­sing all patients’ needs, and in research, is huge­ly impor­tant moving for­ward, and we pro­ba­bly need to do bet­ter at that on a glo­bal scale.

Marianne Guenot