Endometriosis and Adenomyosis Beyond the Sampson Principle - Serdar Bulun, MD

Thank you so much for providing this opportunity for me, and I will get right to it because we have limited time and okay, here we go. So endometriosis happens because of repeated cycles of ovulatory menstruation, and this involves, as you know, hypothalamus, the pituitary F-S-H-L-H, the ovarian action, the ovulation, the response of the endometrium to ovulation, the ovulatory menstruation. And during this process, estradiol and progesterone, they play very important roles. And the pain in endometriosis is mediated through these nociceptors or nerve endings in the peritoneum and sometimes even in the uterine tissue. This is a slide that I borrowed from the top picture from Dr. Kin. It shows that just like any other women, this patient at the time of menses had enormous amounts of blood and also fragments of endometrial tissue in them as the great Dr. S Samson recently, I mean not recently, back in 1920s, have described and all three forms of endometriosis occurs because these tissues may be deposited in an ovarian cyst in the cul-de-sac or on peritoneal surfaces.

This is like work from Dr. Kins group together with Dr. She and also the group from I think University of Washington, very elegantly. What this group did was they mapped the DNA material inside the uterus in endometrium to endometrioid lesions and base payer by base payer. I mean, the chances for this to occur by chance is as low as one in 3 billion. So this was the most definitive scientific proof that the endometrioid lesions originate from the utopic endometrium. Was it only their group? No, it was, this was followed by another Japanese group. In fact, this group went further and said, look, these mutations in the epithelium primarily reside in the Crips of these glands that go all the way down as close as to the myometrium and these all your clones. Then they travel together with blood into the abdominal cavity and they get deposited either involuting corpus, lithium or in other locations.

And was it only this group? No other groups also found the same things? So what I would like to emphasize to you is that there are both stromal cells and epithelial cells that traveled from the intra cavitary endometrium into the abdominal cavity to cause endometriosis. It's the epithelial cells that were originally mutated in the endometrium. And these mutations involve these genes including K-A-S-P-I-K three, ca, arid one A and others. On the other hand, these individuals, they did not find any mutations in the stroma, but that doesn't mean that the strm cells are not abnormal that are coming from the endometrium. They have epigenetic abnormalities. Although the DNA colon doesn't change the way DNA expresses its proteins change tremendously giving rise to these abnormal transcription factors that would cause increased formation of estradiol and prostaglandin. And as you can imagine, prostaglandins do cause pain.

Our group has been instrumental in characterizing how these transcription factors in the stromal cells led to increased Cox two cycl, oxygenase two and aromatase expression, giving rise to more formation of estradiol and prostaglandins. And again, all of these permutations of these cells might be coming to the pelvis from the utopic. Endometrium is that what cell type arrived in the abdominal cavity probably is the factor that determines whether endometriosis is established. And this doesn't stop here. The sister disease for endometriosis is adenomyosis. It's a nasty disease as you can see here. And another Japanese group has looked into this and just like what Dr. Kin and she and Sudan and others have done these groups also in a painstaking manner, they biopsy both the miotic visions as well as utopic endometrium and also endometriosis by the way. And they were able to map these mutations, DNA base pair by base pair in the normal endometrium or utopic endometrium, introduce adeno myotic lesions.

And they did show that when you look at the utopic endometrium in patients with adenomyosis, these patients had a higher, for example, mutation rate for KAS, which was found almost like more than 95% of all adeno lesions. So in case of adenomyosis, the story was a little bit more straightforward. And here I included the mutations that are found in utopic endometrium, adenomyosis and endometriosis as layer myomas. As you can see there, myoma is a totally different disease with respect to mutations, but KRAS gives rise to almost like all miotic lesions, KRAS mutations and most of the endometrium lesions. Although when you look at the endometrium of clinically normal women who do not have these symptoms or endometriosis, PIK three CA mutations are more commonly found.

And we think that the way adeno myosis does happen is that these mutations that accumulate in the deep crips of these glands, eventually through repeated episodes of ovulatory menstruation gets trapped because of myometrial contractions and other inflammatory factor within the myometrial tissue. And form these either islands or they remain at other planes, they remain connected to the endometrial. And what is, I talked about KRA S and what is K-R-A-S-K? RRA S is a mutations, normally we all have KRAS in our body and it's physiologic be required, is a signaling protein and it response to the growth factors that keep cells alive. But if KRAS is mutated, it does bind GTP for prolonged amounts of times and the mutation stops KRAS from self-regulating self to the inactive state. So it keeps cells alive too much and these cells survive. And as a result, probably that's why endometrioid lesions survive.

In other words, I mean this is like the last slide acknowledges the people in my lab and the others. But I just want to emphasize again that now we know beyond doubt that through DNA evidence, which is used in the court as you know, to prove or disprove crimes, now we have DNA evidence irrefutable DNA evidence that Samsung was correct. So we need to embrace this as a group of scientists and doctors and patients in endometriosis so we can move forward. So again, 99% of all pelvic endometriosis originates from the cells that work in the eutopic ome. Thank you for providing this opportunity for me. Bye-Bye.