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.

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