International Medical Conference Endometriosis 2025:
Endometriosis 2025: Your Mother Should Know, Your Doctor Should Know Better!
Ovulatory Menses and Endometriosis - Serdar Bulun, MD
I'd like to introduce Dr. Serdar Bulun. He is a professor and chair of the Department of Obstetrics and Gynecology at Northwestern University. He is a member of the National Academy of Medicine. He's renowned for his groundbreaking work on research on the role of estrogen in endometriosis and aase inhibitor as treatment. Thank you.
Serdar Bulun, MD
Thank you. I would like to thank the organizing committee and Dr. Seckkin for having me. Here is a real honor, and today I would like to emphasize the role of ovulatory menses and the events that we normally observe as regular gynecologists and why they're important for the pathophysiology of endometriosis. And before that, I would like to start by emphasizing that an average patient with endometriosis, the symptoms almost always starts in the teens most of the time with painful menses. And in their twenties, these patients, they have chronic pelvic pain, painful intercourse if they're parents or doctor or insurance supports, they might have their first laparoscopy and diagnosis, which we now question whether this laparoscopy is necessary anymore to treat endometriosis. And then these symptoms may dwindle or may even get worse into their forties and fifties. And here they go, repeated attempts of oil contraceptives and s aids, progestin, IUD, and the lucky patient, their pain gets treated with one of these, including laproscopy resection. And usually the treatment naive patients are the best. They respond. But then in a large number of these patients, the symptoms recur. And these are the challenging patients that we always see and try to help.
Again, most of us are familiar with this pathway and there's ample evidence, and I'll go over some of them now. There's DNA evidence that endometriosis almost like 99% of it originates from eutopic endometrium, either in peritoneal tissues or in the ovary or deep infiltrating endometriosis. And this process, I mean all the medical treatments that we have targets the brain, GNH or FSH, so that they would not stimulate the ovaries to make estrogen and progesterone. But also, like today, I will talk about this also causes a terrible withdrawal bleeding that contributes greatly to endometriosis. And this is the original work of Dr. Kin and his friends. And I just put this here to emphasize that this painstaking work, they biopsy everywhere. They biopsy eutopic endometrium, they biopsy deep infiltrating endometriosis. They biopsy ovarian endometriomas. And they looked for DNA evidence for mutations, somatic mutations. And their work was replicated by others.
And these other groups, they looked more carefully in utopic endometrium and they found these clones, small clones of cells, which were hiding in these deep Crips. And they were like, they had these somatic, somatic mutations are not the kind of mutation you can pass on to your next generation, but they're there. And these mutations were, they had to look very carefully in utopic endometrium because it's a vast tissue compared with endometriosis osis. They found that these mutations are overrepresented in endometriosis number one. Number two is like when they looked at base pair by base pair, they found mostly the same mutations demonstrating that this DNA here in endometriosis originated from this DNA.
To make a long story short, there are two types of problems in endometriosis molecular problems. One is these mutations that I described, and they change the function of a protein or it kills the function of a protein because the base pair changes, the protein sequence changes. The second type of epigenetic abnormalities is my lab and a lot of other labs contributed greatly. And this is how this DNA is read. The DNA in my retina in my eye is the same DNA in my liver, but they look totally different. That's because some of these genes are shut down in certain tissues while they are upregulated. In others, we found a similar situation in endometrioid stromal cells. The genes that should be shut down were not shut down. And the genes that should be upregulated like progesterone receptor was downregulated.
We kind of also looked at the mutations that were found in adenomyosis, which is a assisted disease to endometriosis in many ways, both clinically and molecularly. It's just that in adenomyosis, most of us agree that there is some sort of a trauma that leads to entrapment of especially utopic endometrial bacterial cells and a little bit stronger within the myometrium and probably for trauma. Look no further, like repeated episodes of menstruation themselves, in my mind is trauma. And so what happens is if these mutations, like K RRA S mutations give survival advantage to these cells, then they survive in myometrium. And that's what we call adenomyosis. And I think this group published the most important paper on adenomyosis from Japan and colleagues. They found that they looked at like they did similar work to Dr. Kins and others, and they found that yes, eutopic endometrium, DNA or mutations, they are represented in, for example, both in adenomyosis and also in endometriosis.
But they look further to utopic endometrium. They did some statistical analysis to see the endometrium of patients with adenomyosis, patients with endometriosis and patients with none of these diseases. As you can see, one of these mutations, PIK three ca, is pretty much well represented in both utopic endometrium and endometriosis to similar amounts. But when you look at this KRAS, it is overrepresented almost exclusively overrepresented in adenomyosis and somewhat in endometriosis. So this was like, again, they provided additional DNA evidence that the endometrium is a source for these lesions. And again, I'm not quoting all the other labs. And there's another independent lab from China. In fact, they published the first paper in 2014, and their work went fairly, went unrecognized until this New England Journal of Medicine publication of Dr. Kins to put all of these things I, this KRAS mutation in epithelium seems to be important both for adenomyosis and endometriosis, and they have nothing to do with fibroids. As you can see, the fibroid mutations are ME 12 and ME 12 was never found in adenomyosis or endometriosis. But these are like sister diseases.
Some of our work. Before I went into ovulatory menses, we found this pathway whereby prostaglandin E two that causes pain in endometriosis was instrumental in stimulating estradiol production within the endometrioid tissue and estradiol per se, through estrogen receptor beta induce COX two. And we demonstrated this vicious cycle, which was important because if you treat these patients with COX inhibitors or rase inhibitors, their pain went down. And we also demonstrated that progesterone resistance is key because it further suppresses the metabolism or inactivation of estradiol. I'm going back to menstruation and ovulatory menstruation. Ovulation does something else.
The estradiol levels in the graphene follicle is immeasurable, probably. It's in the, it says high as 130,000 picograms for ml. It's huge. And think about that. All of this estradiol is released into this soup. This is like Dr. Kin provided me this picture and I'm grateful to him. It just demonstrates everything. This is one of the scopes he did right after menstruation of a woman. You can see that there's blood here, and probably in this blood there is enormous amounts of estradiol that was released into it. And there are pieces of this mutated endometrium tissue swimming in the soup, almost like what Samson described a hundred years ago.
Going back to ovulatory manes. Why is that important? Because think about endometrium. It's not like endometriosis, like more than hundreds of layers of these stromal cells in endometrium, right before menstruation. And then these crips, these epithelial cells, there's a single layer of epithelial cells. It kind of gets into these deep crips, but they're not really glands. I mean, they eventually, they connect to the lumen. But think about it, how much, and then of course, there's the biology of spiral arteries, right? The only, the species who have spiral arteries, they get spontaneous endometriosis. My don't get endometriosis spontaneously. Monkeys do, old world monkeys do. And they do have these spiral arteries, and they're important because they are regulated by estrogen and progesterone. And this immense amount of necrosis in this layer, which leaves this tissue intact and alive, and all of this stuff goes back into the, some of it goes back into the peroneal cavity. So now think about another situation in which there is withdrawal bleeding after oral contraceptives or postmenopausal hormone replacement that looks like this.
The endometrium is already in doubt. There are bits and pieces of epithelium here and there. Usually what these patients experiences, blood is sort of like going through the cervix and vagina, and maybe some of it may go through the tubes. That's why patients on oral contraceptives, even if they would go through withdrawal bleeding, they're not at high risk for developing endometriosis as the epidemiologic data shows. So I think I'm going to stop here and acknowledge some of my lab and my collaborators and many other collaborators that I did not list here to contribute some of this work. Thank you so much.
