Endometriosis Is Common. Why Is Getting Diagnosed So Hard?

FLORA LICHTMAN: Hi, this is Flora Lichtman, and you’re listening to Science Friday. Today on the show, we’re talking about a condition that many women have a story about.

AUDIENCE: Hi, this is Emily calling from Colorado.

AUDIENCE: Hi, my name is Melissa.

AUDIENCE: Hi my name is Anna from Chicago.

AUDIENCE: Bonnie from Madison, Wisconsin.

AUDIENCE: Ellen from Cape Cod.

FLORA LICHTMAN: And that story often goes something like this.

AUDIENCE: I spent about four years trying to get diagnosed.

AUDIENCE: I had a 10 year round with it before we found somebody who knew something about it. I was diagnosed after suffering for 20 years, almost.

FLORA LICHTMAN: It’s an extremely common condition. If you have a uterus, you have a 1 in 10 chance of getting it. And yet.

AUDIENCE: My symptoms were dismissed by my male gynecologist.

AUDIENCE: I feel like it took a long time for my OB to take me seriously.

AUDIENCE: It actually almost killed me.

FLORA LICHTMAN: We’re talking about endometriosis, a painful disease that occurs when endometrium-like tissue grows outside of the uterus. What does the latest science tell us about the biology of the condition and how to treat it? And why do so many people have such a difficult time getting diagnosed?

Here to answer these questions and more is Doctor Linda Griffith, who spent the last 15 years studying endometriosis. She’s a biological engineer and scientific director of the MIT Center for Gynepathology Research, based in Cambridge, Massachusetts. Linda, welcome to Science Friday.

LINDA GRIFFITH: It’s great to be here.

FLORA LICHTMAN: How do you define endometriosis? What’s happening in the body? And what are the symptoms?

LINDA GRIFFITH: So endometriosis is a disease where bits of tissue that resemble the endometrium are growing throughout typically the abdominal cavity on the bowel and so on. So there are a constellation of symptoms. Usually there’s very severe menstrual pain, often heavy menstrual bleeding.

But a lot of times there are gastrointestinal problems, and those problems can actually commence before a girl starts her period. So when we say that endometriosis is a disease of women, we should be inclusive and say women and girls because the onset of symptoms around the time of menarche often presages diagnosis of endometriosis, soon after, if not, then decades later, as happens to many women.

FLORA LICHTMAN: Why, oh, why is this story so consistent that it takes years, sometimes decades for people to get a diagnosis?

LINDA GRIFFITH: There are probably many reasons. I’d say one is that we have a squeamishness about menstruation in general, so you don’t want to talk about it. It’s supposed to be a natural process menstruation. So if someone has an extreme experience, they’re often dismissed as being dramatic or making things up.

And oftentimes, if doctors don’t have a measurement that lets them see a condition or a disease where they can measure it– like with diabetes, you have blood parameters, glucose and insulin and so on. With heart disease, there’s all kind of imaging.

Endometriosis does not have a definitive set of metrics in order to diagnose it, and so it’s often by a process of elimination that you ultimately get to surgery, which is a huge step and the definitive diagnosis.

FLORA LICHTMAN: You didn’t start out your career wanting to study endometriosis. What made you change course?

LINDA GRIFFITH: It was a whole collision of factors. Not long after, I won a MacArthur Award. First you’re supposed to do something new and creative.

But at the same time, my niece started having symptoms as soon as she started her period when she was 12, and she was dismissed and sent for all these GI tests. And finally her doctor told my sister, your daughter is making things up to get out of going to school. And this made my head explode because I myself had experienced this, and I wasn’t diagnosed until I was 28. And it was accidental when I was diagnosed.

FLORA LICHTMAN: With endometriosis?

LINDA GRIFFITH: Yes. I got diagnosed accidentally and only because I went to a doctor every month for six months insisting that my symptoms were not normal. And I ended up having an accidental diagnosis. No one ever mentioned it.

They said I’d have surgery and be back at work in a day or two. And I didn’t even wake up for a day because I had such severe endometriosis. I had to stay in the hospital for a week after having an open procedure.

And I had told the doctor. I thought my niece had endometriosis, and she argued with me. So I got her refer to a really good surgeon in Atlanta, and she had stage III endometriosis when she was 16.

And there’s something about the maternal instinct where you can tolerate something that happens to you, and you can get through it. But when you see something that happens to your child– and she’s not my child, but I’m very close to her– it just– I went ballistic. And the surgeon who operated on me the past four times had been imploring me to work with him.

And he kept saying, there’s been no progress. We still have the same drugs we had forever. Animal models don’t work. You’ve got to bring new approaches. Engineering, certainly MIT can do something about this terrible disease.

And it was really that that pushed me into thinking, oh my gosh, of course I’m an engineer. There are things I could probably do that haven’t been done before. So why don’t we give it a try?

FLORA LICHTMAN: Because you are a tissue engineer, right?

LINDA GRIFFITH: Yes. So I started my career in what we would call regenerative medicine at the very early days, thinking that we would build all kind of approaches to build livers for transplant. I actually was a co-inventor on the original three-dimensional printing process for making scaffolds for bone wound healing and got things into the clinic. I created the human ear on the back of the mouse, which your older listeners may remember.

FLORA LICHTMAN: We remember, yeah.

LINDA GRIFFITH: I did a lot of things in the regenerative medicine space, but I had an epiphany that there are so many chronic inflammatory diseases that we don’t how to treat. So I started building models of human organs and tissues in the lab using what we call microfluidic chips.

And when I got asked about endometriosis, it was actually a perfect application for this kind of approach because we really need to study the lesions very carefully in the lab in ways that’s very hard to study in patients. So it was actually a good match for the things I knew how to do.

FLORA LICHTMAN: These are the lesions that grow outside– they’re endometrium-like tissue that grow outside of the uterus, and this is what causes the pain.

LINDA GRIFFITH: Yes. So what we don’t precisely what causes pain, but anytime you have inflammation from an irritant, it can be painful. Just think how bad it is if you get a splinter in your finger. It hurts a lot, especially if you whack it on something.

And so even a little tiny lesion thing can cause immense pain because nerves grow into these lesions. You have immune cells there, and the immune cells and nerves are talking to each other and creating quite a ruckus. And if patients suffer from these lesions– and it may be one.

It may be many. They may be small. They may be large. They may infiltrate into your bowel wall.

There’s many, many different manifestations of these lesions. It’s quite remarkable. I’ve been to probably 100, 150 surgeries. And every patient is different, but the appearance of lesions is always is really, really shocking that they grow like that.

FLORA LICHTMAN: And they can grow very far away from the uterus too, right?

LINDA GRIFFITH: So some of the most surprising things to me when I started watching surgeries, lesions can grow in your diaphragm, your breathing muscle. And the lesions will invade through the diaphragm and get into what’s called the pleural cavity, the region that surrounds your lungs. They can grow along the sciatic nerve and cause enormous sciatica.

And what’s fascinating to me as an engineer and someone who studies biomechanics is they almost always are attracted to tissues that have a muscle and a muscle that contracts. So think of your intestine. It is always contracting to move food through. Your bladder is contracting your diaphragm. Of course it’s contracting because you’re breathing and so on and so on.

And you rarely see the lesions in places like the liver, the omentum, the mesentery, organs that ovarian cancer often invades are rare spots that you see endometriosis. So there’s some really interesting scientific questions about the kind of neighborhood these lesions like to be in and ways that we can build that neighborhood in the lab so we can study the nature of these lesions and their native habitat but outside the body in the lab.

FLORA LICHTMAN: What goes wrong to cause this condition? Do we know?

LINDA GRIFFITH: If we knew, maybe we would cure it. What we have are many clues. But we don’t know why some people get it and some don’t, but we can speculate on the origins from a tissue level.

So the two main theories are as follows. One is so-called Sampson’s hypothesis, and this takes account of the fact that most women, when they have their period, some of the menses that shed endometrium goes out the fallopian tubes into the peritoneal cavity. And so the theory goes that this tissue in some women can implant on the abdominal cavity or on the ovary. And that is an appealing explanation for the origins, and I personally do believe that some women, probably even myself, had this as part of their etiology of disease.

The other main hypothesis is that it is a developmental origin. So when your body develops, some cells travel long distances by cell migration, and they travel together. But every now and then, some of them go astray. So sometimes in development there can be interruptions of these signals, and you don’t get fully formed organs. And we see this all the time. People who have a cleft palate had a developmental abnormality.

And so one hypothesis posits that there are cells that are destined to become endometrial cells that fall off the train on the way to their destination. And when your body goes through puberty, they wake up, and they form these lesions.

FLORA LICHTMAN: So when you say developmental, does that mean that you have a genetic irregularity that causes this to happen? What does developmental mean exactly?

LINDA GRIFFITH: So developmental could mean you have a genetic predisposition. It also could mean your mother got some infection or exposed to some chemical or stress, something. There’s many, many different potential impacts on the developmental process that are not strictly your genes that you inherited from your parents because interaction between environment and genes is very important.

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FLORA LICHTMAN: After the break, what scientists are learning from growing endometriosis lesions in the lab.

LINDA GRIFFITH: So it’s pretty high-tech stuff that I myself have a hard time believing sometimes we can actually do.

FLORA LICHTMAN: So we talked about your work in tissue engineering. How do you apply it here? Because it seems like a very complex system. We’re not talking about one organ. It’s not just the uterus. So how does it work?

LINDA GRIFFITH: So I’m an engineer, and one of the things engineers do is develop what we call design principles or common themes in what may look very diverse processes. So you can say, all right, these lesions are growing in locations that have certain properties. What’s its hormone environment? What’s its immune environment?

And now I’m going to bring the cells from the patient. And we can get cells from the lesion itself. We can get her eutopic tissue and make organoids from it and combine it with other cells because there’s many different cell types. And we use some extremely powerful and advanced tissue engineering and microfluidic tools to create what we call a platform that allows us to pump culture medium around and through the lesion. So we create little blood vessels that feed the lesion, and we put it in a microscope system that lets us watch it actually grow over time.

FLORA LICHTMAN: So you have lab lesions. You’re making lesions in the lab.

LINDA GRIFFITH: We make lesions that represent the patient in the lab. And we’re talking about a big piece of tissue that has blood vessels that we grow from scratch. So it’s pretty high-tech stuff that I myself have a hard time believing sometimes we can actually do.

FLORA LICHTMAN: And presumably, if you can grow the lesions in the lab, you can then understand both why they form and maybe how to interrupt them?

LINDA GRIFFITH: So we’re further away from understanding why they form precisely. But we really are focused on, how can we interrupt them? And specifically, how can we do it in a way that is personalized for the patient?

Because even though we don’t understand so much about the genetics of why you might get endometriosis, there are genetic signatures associated with the probability you will have the disease. And so we can take samples from patients with different genetic backgrounds or other features that we may identify in the clinic and say, OK, we’ve got these four different groups of patients.

Group A has common features. Group B has common features, but they’re different than Group A. So we can create different groups of patients. And I think that’s the really powerful thing about our model is we can link genetics back to real phenomena that may be operating in disease by building this very complex model that captures so many different features of the immune system, the nerves, and the lesions interacting.

FLORA LICHTMAN: So how is endometriosis currently treated?

LINDA GRIFFITH: So the first-line treatment, meaning a patient has symptoms that would be suggestive she might have it, is you’re given some kind of birth control pill that has a progestin-like activity to oppose estrogen because estrogen is pro-growth. So you want to suppress estrogen, and the theory goes that you will suppress then the symptoms and so on.

So some patients will respond to that. But if they don’t respond or if the side effects are too severe, then you might progress them to a more powerful drug, something called a GnRH antagonist, which will shut off the pituitary axis and cause a menopause-like state. And that will help some patients.

But again, the side effects are very serious. And then there are a couple other therapies. But generally, patients, if they have intolerable symptoms, are considered for surgery.

Along the way, imaging will be done, and imaging is getting better and better. But it’s not definitive. So you can certainly see large lesions like endometriomas, cysts on the ovary. Certain kinds of lesions that are in the bowel you can often see.

But 70% or so of patients have tiny lesions that you can’t really see on imaging, at least by the standard radiologist, unless they’re extremely highly trained. And so in that case, the patient would go to surgery based on her symptoms, and then you would see what’s there and take it out and send it to pathology.

FLORA LICHTMAN: Tell me, so what is on the forefront for treatment?

LINDA GRIFFITH: So I’m very excited about the number of companies that are zeroing in on various biological processes. One of them involves inflammation pathway I’m very familiar with because my group identified it in patients very early, 2014, in a high-profile publication.

And it turns out a colleague in industry was developing drugs that target that exact pathway, and he now has really, really good molecules that we’re actually testing them in our little lesion models in the lab. And I think that they’re very, very promising because they go after a very fundamental part of the process that causes inflammation and lesions, and they have the opportunity to work potentially in a large group of patients. You never until you go to the clinic. But I think they’re very, very promising.

And that’s just one pathway. And different patients may have different pathways that are dominant. So I’m optimistic that a year from now or two years from now the number of clinical trials will hopefully drive better outcomes.

I think the other thing is there’s enormous, enormous activity in the space of diagnostics, Diagnostics that might be based on menstrual blood, for example. Really exciting things going on. Nothing that’s ready for prime time. But definitely a lot of big brains are in that space and something I think will happen.

FLORA LICHTMAN: Doctor Linda Griffith is a biological engineer and scientific director of the MIT Center for Gynepathology Research, based in Cambridge. Linda, thank you so much for joining me today.

LINDA GRIFFITH: Thank you so much for having me.

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FLORA LICHTMAN: Today’s episode was produced by Shoshannah Buxbaum. I’m Flora Lichtman. Thanks for listening.

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