Melanie Cole (Host): Endometriosis is one of the most common conditions seen in practices today and can be a painful, but manageable gynecological condition. My guest today is Dr. Serdar Bulun. He’s the Chair in the Department of Obstetrics and Gynecology at Northwestern Medicine. Dr. Bulun, tell us a little bit about yourself and how you came to Northwestern Medicine.

Dr. Serdar Bulun (Guest): Yes, I was originally trained in obstetrics and gynecology followed by fellowship training in reproductive endocrinology and infertility. Starting early in my career, I have been working on endometriosis and conducting basic and clinical research studies on this challenging disease. My team and I started to work on endometriosis in 1993 at the University of Texas at Southwestern Medical Center in Dallas. Thereafter, we moved to the University of Illinois at Chicago. In 2003, I moved my research operations to Northwestern University, Feinberg School of Medicine, and of course Northwestern Medicine where I have stayed since then. Currently, I proudly serve as the Chair of the Department of Obstetrics and Gynecology at Northwestern and continue to run a sizable laboratory concentrating on common gynecologic diseases, namely endometriosis and uterine fibroids. I should point out that our department ranks second in the nation for NIH funding and a substantial portion of these funds are devoted to study endometriosis. My work on endometriosis has been acknowledged both nationally and internationally, as evidenced by my recent election to the National Academy of Medicine.

Host: Doctor, before we get into some of the advances made to treat endometriosis, why does it often go undiagnosed or misdiagnosed?

Dr. Bulun: The most important reason is that its current definition is not helpful or useful for diagnosing the disease or managing it’s symptoms effectively. The term endometriosis has been traditionally described as the surgical demonstration of endometrial like tissue that is the inner lining of the uterus outside of the uterine cavity primarily on lower abdominal organs and ovaries. This narrow anatomic definition; however, is not sufficient to explain it’s natural history and duration, the full spectrum of it’s clinical features, the frequent recurrence of her symptoms, the underlining causes, or responsiveness to hormonal treatment. Unfortunately, this narrow and unhelpful anatomic definition can lead to confusion about the treatment options and even denial of hormonal or surgical treatment to endometriosis treatment who may not have recognizable pelvic peritoneal lesions at the time of laparoscopic surgery. Thus, this classical definition of endometriosis needs to be modernized to a more patient focused version that recognizes the cellular and molecular origins of these, it’s natural history from teenage years to menopause, it’s complex, chronic and systemic nature, the variety of tissues involved including the central nervous system, I should emphasize and the need for long term management. Most of the time, endometriosis starts as extremely painful periods that we call dysmenorrhea during teenage years or a young woman, and then these symptoms develop into chronic pelvic pain. Almost 99% of endometriosis occurs in the pelvis, that is the lower abdomen and this happens because of backward travel of menstrual material including blood and endometrial tissue fragments through the tubes, into the pelvic cavity, and then these tissues implant in the pelvis and continue to respond to steroid hormones, estrogen and progesterone in an abnormal way and cause intense inflammation and pain. Unfortunately this simple mechanism of disease usually is not seen as a whole, but bits and pieces are addressed differently during different portions of a lifetime of a woman, and to me this is the biggest obstacle as to why we do not diagnose or manage it well because the management of endometriosis, first and foremost requires suppression of ovulation and menstruation – as clinicians we should appropriately redefine endometriosis as a complex clinical syndrome characterized by estrogen dependence, chronic and painful inflammatory process that affects primarily pelvic tissues including ovaries and are strongly linked to recurrent pelvic pain and persistent episodes of ovulation, menstruation, and cycling steroid hormones. We should remove the requirement for surgical visualization of pelvic implant at least before we can start hormonal treatments that suppress ovulation.

Host: What are some of the complications of this condition? Can endometriosis lead to other conditions? Can it lead to ovarian cancer?

Dr. Bulun: I think there’s an undeniable and very important link between endometriosis and ovarian cancer. This link is not readily recognized because persistent endometriosis in the ovary that may start during the teenage years may act as a seed for ovarian cancer for some 40 or 50 years later. This concept recently became more plausible because driver mutations of ovarian cancer, they’ve been recently demonstrated in intrauterine endometrial tissue as well as in ovarian and extraovarian endometriosis tissue. Interestingly these identical mutations were also mapped to most ovarian cancers. This makes sense because pelvic endometriosis occurs primarily as a result of backward menstruation of mutated endometrial cells and the implantation in ovarian inclusion cysts and they may stay there almost forever. The inflammatory and estrogen rich environment must be unique for turning these mutated cells into cancer because they do not turn cancerous if they are outside of the ovary.

Host: That is so interesting, Dr. Bulun. Tell us about some of the advances made to treat endometriosis. What are some of the new medications available? Please speak about any that you know of, including Orilissa, elagolix, I mean I think those are the same thing, but speak about some of these medications we might have heard of.

Dr. Bulun: Yes, the most important component of endometriosis management is just prevention. In other words, if we prevent menstruation, which also involves the backwards menstruation through the tubes of the blood and endometrial tissue fragments implanting in pelvis, then we would make a major impact in preventing the formation of endometriosis. Once endometriosis is established and causes the inflammation and pain, the management and treatment are much more difficult. A lot of surgeons would agree that surgery on endometriosis could be much more challenging than for example surgery of ovarian cancer because endometriosis causes intense inflammation and adhesions of these different tissues including the bowel to uterine and ovarian surfaces. They all kind of like stick together, and they are very difficult to dissect surgically. Before the disease becomes advanced enough to require difficult surgery, we would have enough opportunity to prevent it from coming to that stage, and again this would involve identification of young women during their teenage years, especially those who experience extreme pelvic pain during their periods and suppressing their periods using simple measures such as birth control. If the birth control pill is not sufficient then other medications are available to suppress the ovulation and the periods such as GNRH agonist or the new oral antagonist. In particular the new oral GNRH antagonist named elagolix, or Orilissa, has been recently introduced into the market after it’s FDA approval in 2018. Long term use of GNRH antagonists may cause osteoporosis and everybody should be aware of this too.

Host: Tell us a little bit more about birth control to stop ovulation and the aromatase inhibitors.

Dr. Bulun: Unfortunately an average patient with endometriosis suffers from symptoms for decades. Severe menstrual pelvic pain initially experienced during the teenage years gradually evolves in quality and severity as the influent stimuli from pelvic disease persists and the peripheral and central nervous system is continually reconditioned. Newly diagnosed patients with endometriosis significantly benefits from medical or surgical treatment, and almost like all treatment naive patients, that means patients who have never been treated before, achieve pain relief, almost 100%, but the problem is the pain recurs in 6 months to 2 years and these patients return for more treatments. Thus at any given time, birth control pills or GNRH agonists or antagonist or surgery can treat endometriosis associated pain at best in only half of these patients but the other half become resistant or refractory to these treatments over time. So the challenging part is to provide pain relief for this patient group who are refractory. In our laboratory, we discovered that estrogen is the driver for inflammation and pain in endometriosis, thus we targeted estrogen formation to give a little novel treatment. Birth control pills can stop estrogen made in the ovary, but estrogen is also synthesized or manufactured outside of the ovary. For example, in endometriosis tissue itself. So to stop estrogen formation outside of the ovary, we add an aromatase inhibitor to the birth control pills to effectively deny estrogen to diseased tissue. This provides additional pain relief in these patients who were previously refractory to the conventional treatment. Thus using our basic research and clinical experience together, we single handedly introduced aromatase inhibitors as a novel class of medications to treat endometriosis. In our hands the first lines of therapy is a continuous oral contraceptive or a birth control pill because these are sustainable treatments. You can maintain your patients on an oral contraceptive for years, even decades. They have some side effects but they are mostly manageable. If the patient is not responding to this treatment, then there are other options. You may be able to add an aromatase inhibitor to decrease estrogen production even further while the patient is on an oral contraceptive and this may be sufficient to stop or reduce pain to a manageable level.

Host: When or if should surgery be considered?

Dr. Bulun: It’s important to establish that the most important symptom that we treat in endometriosis is pain and at the same time, if the patient desire fertility there’s various fertility treatments such as in vitro fertilization. For now, we are going to talk about pain. Whether we establish there is endometriosis that is visible by laparoscopic surgery in the pelvis of a women or not, the backbone of the treatment is always to suppress the period using birth control pills plus or minus an aromatase inhibitor. Surgery by laparoscopy should be used judiciously and as little as possible. An average patient with endometriosis may have to go through a laparoscopy and surgical removal of endometriotic implants in her pelvis about every 5 to 10 years. The less surgery, the better it is for these patients because the surgery, as in many other treatment modalities, also has a lot of side effects. This should be done only by a surgeon experienced specifically in endometriosis surgery because if the surgery is done suboptimaly the symptoms will be more likely to come back.

Host: Dr. Bulun, as we wrap up, what a fascinating topic. Please tell us about any research that would impact the future of treating those with endometriosis and what you would like providers to know and take forward to help their patients.

Dr. Bulun: It should be established that endometriosis is a chronic illness, as other chronic illnesses such as inflammatory bowel disease or rheumatoid arthritis. Endometriosis cannot be cured by either surgery or hormonal suppression. Many times it will relapse mostly as pain or rarely by other means such as blocking the ureters and kidney failure; therefore, it’s management should be viewed as long term and the mainstay of treatment should be suppression of ovulation. There are other futuristic advanced treatments that are in the works. All women menstruate backwards through their tubes in the lower abdomen during their periods, but only 10% of them develop endometriosis. This still is a very, very large number. We estimate that 5 to 10 million women in the United States at one given time suffer from endometriosis. In these 10% the intrauterine endometrium contains effective and progesterone hormone resistant stem cells that inappropriately survive in the abdominal cavity, whereas in disease free women, these cells get absorbed or removed by normal hormonal or immune mechanisms of the body. Some few decades from now, it may be possible to replace the defective intrauterine endometrial cells of the patient with normal differentiated ones using cell based treatments so that when backwards menstruation occurs, these cells would not implant or cause inflammation in the pelvis. In fact, our group made a breakthrough progress to take the first step towards this goal. We were able to take either blood cells or skin cells of a patient, erase their existing DNA program to make induced pluripotent stem cells that we call IPS cells. Then we properly program these IPS cells to make normal and appropriately progesterone responsive endometrial types of cells and we just published our findings in the Journal Stem Cell Reports in 2018. We are hoping that this kind of technology will allow different approaches to treat endometriosis. One day we will be able to replace the defective stem cells in the endometrial cavity of a patient with these normal ones generated from the patient’s skin tissue so that these cells would no longer cause inflammation or pain if they would go backwards into the pelvic cavity.

Host: Wow, what great information Dr. Bulun. Thank you so much, the research that you’re suggesting and examining is really so very interesting for other providers to hear. Thank you again for joining us and sharing your expertise on the latest advances in endometriosis treatments. This is Better Edge, a Northwestern Medicine Podcast for physicians. For more information on the latest advances in medicine, please visit nm.org, that’s nm.org. This is Melanie Cole, thanks so much for listening.