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Warner Huh, MD: Hello, everyone. This is Dr. Warner Huh, the Chair of Obstetrics and Gynecology here at the University of Alabama at Birmingham. I hope you all had a wonderful Thanksgiving holiday. I want to welcome you to this monthly episode of Women's Health with Dr. Huh.

So today, I'm super excited to talk about a topic that I know is important to our guest speaker today. It's the topic of endometriosis and associated infertility. I'm also excited to introduce our next speaker, Dr. Richard Burney, because he's our new Division Director for Reproductive Endocrinology and Infertility here at UAB in the Department of OB/GYN. He's also an associate professor in the department.

You know, just a brief background on Dr. Burney, he is an Auburn, Alabama native, and really spent the majority of his career in the military, specifically with the Army and has been in Tacoma, Washington at Madigan Army Medical base for many, many years. And he attended West Point for college and did his infertility fellowship at Stanford University. So, I'm super excited to have you join us, Dr. Burney, today.

Richard Burney: Happy to be back in Alabama. Happy to be at UAB and I'm thrilled to be on the podcast this morning.

Warner Huh, MD: Well, great. So, let's dive right into it. So, I think many of our listeners have heard the term endometriosis many, many times. But just for a good place to start and educate our listeners, can you just talk about what exactly endometriosis is and perhaps, you know, how common is it, what women should look out for?

Richard Burney: Yeah, it's a great way to lead in. You know, in fact to your point, what is endometriosis was actually the third most Googled health question of 2018. Not many people knew that with over 31 million queries. So, public interest and inquiry in this condition is definitely on the rise. But it remains what many refer to as an enigmatic disease due to the many perplexing features associated with the condition. In fact, this condition has been described for over a century, but the exact pathophysiology and pathogen of the condition is still a matter of debate.

Interestingly, about 73% of the world's medical literature on the subject of endometriosis has been published over just the last 25 years. So, a lot of important advances have been made, yet a lot remains to be learned about developing novel diagnostic, preventative, and even therapeutic approaches to endometriosis.

So, what is endometriosis? Well, it's a common gynecologic condition. It affects about one in 10 reproductive-aged women. In the general population, about one in three women who have otherwise unexplained infertility. It's defined by the presence of uterine lining, which is also known as endometrium, in locations outside the uterus. So, predominantly the lining of the pelvis, ovaries, intestines and bladder. But interestingly, and this is one of those perplexing features I mentioned, endometriosis could also be found in more distant sites than just the pelvis. Sites like abdominal incisions, the lungs and, in rare cases, even the brain.

To understand the disease, I think it's really important to review a few fundamentals as well as some unique aspects of human reproductive anatomy and physiology that predispose women to endometriosis. So, bear with me, I'm just going to go through a few of those points.

First, the uterus or womb, it's lined by a lining known as the endometrium. And the endometrium is a fascinating tissue in so far as it's turned over monthly. It's comprised of cells that include glandular and stromal cells. In fact, the pathologists make a histopathologic diagnosis of endometriosis on the basis of finding these endometrial glands and stroma in biopsies of sites, lesions that are located outside the uterus. So, that's the formal definition of endometriosis.

In women with normal menstrual cycles, the endometrium grows in thickness to support a potential pregnancy. But if that pregnancy doesn't happen, the lining shed in a process that we refer to as menstruation. And that menstruation is fundamental to the development of endometriosis. It's physiologically unique, interestingly enough, the process of menstruation, to very few mammalian species and those are the only species that are known to spontaneously develop endometriosis. So, menstruation is really fundamental to the development of this condition.

During menstruation the majority of the lining is actually shed out the cervix as menses in an antegrade direction. But surgical studies that were performed in the mid-1980s showed that in 94% of women, so almost a majority of women, menstrual product is also released via open fallopian tubes into the pelvis in a process that we refer to as retrograde menstruation. This was a phenomenon that was first described in the medical literature by a surgeon named John Sampson in 1927. Now, it's accepted to be the most widely supported method by which endometrium gets released into the pelvis. In the majority of women, that retrograde menstruation product that gets out into the pelvis is not a problem because it gets cleared by the immune system. But for reasons that remain unclear, in about 10% of women, those lesions don't actually clear, instead that tissue actually implants onto the lining of the pelvis or other organs and becomes what we refer to as an endometriotic or endometriosis lesion. And true to their endometrial origin, the lesions themselves, they continue to menstruate in their new anatomic location. Knowing that they're from the endometrium, they continue to be endometrial-like, and literally shed during the menses of subsequent periods. And this predisposes to development of pain during cycles called dysmenorrhea, also predisposes to adhesion formation in these patients.

The lesions grow locally. They form their own new vascular and nerve bundles, which can lead to chronic inflammation and other non-menstrual types of pain, such as pain with intercourse or dyspareunia. And that altered inflammatory environment in the pelvis sets the conditions for disordered hormonal pathways and consequent abnormal uterine bleeding, particularly spotting before the onset of full menstrual flow. And this is a symptom of endometriosis that's getting more and more attention, is the presence of spotting before the onset of full menstrual flow as a harbinger of pelvic inflammation and endometriosis.

Interestingly, there are three different forms of endometriosis now described. And there's increasing evidence that these different forms may develop by different mechanisms or different pathogenesis.

One form is peritoneal, and these are the lesions that are found in the lining of the pelvis. Ovarian endometriosis describes the form of the disease in which a lesion actually menstruates into the ovary to create a fibrotic cyst, which is referred to as an endometrioma or chocolate cyst as it's also known. And then finally, the more recently recognized form in the literature is referred to as deep infiltrating endometriosis. These are lesions that are located in deeper layers.

So, endometriosis is surgically staged. It's not cancer, but it's kind of staged like a cancer in so far as it's got a one through four staging system with stage I being minimal disease, typically peritoneal and stage IV being the more severe form of the disease, typically highlighted by endometriosis affecting the ovaries and pelvic adhesions. But most women actually engage their healthcare provider due to chronic pelvic pain and fertility concerns.

Warner Huh, MD: You know, I had no idea that it was that common of a medically searched term in Google. And it's interesting, I think in women's health, we probably see some of the most common conditions in all individuals and, obviously, endometriosis and then other fibroids are really right up there. But what's remarkable to me is that, that number that you quoted in terms of incidence, is probably on the low side because there are probably thousands of women out there that have endometriosis who have no idea they have it. And in fact, it's remarkable to me, I will operate on women who have endometriosis and they had no idea and they have very minimal symptoms. And so, I think it's important to recognize that it's probably under-recognized overall in the community.

So, for our listeners, Dr. Burney, I thought it might be helpful if you could just comment on how endometriosis is generally worked up and then managed. And, you know, I think you and I both know that they're both surgical and non-surgical approaches to management, so I thought you may want to comment on those two things.

Richard Burney: That's a great question. I'd highlight at the outset that endometriosis diagnosis is rendered more challenging, and this is probably why it's underreported as far as the prevalence due to the absence of a convenient laboratory test to detect the condition. And this is a gap that's resulted in a near seven to 10-year latency from the onset of symptoms to definitive diagnosis. As a consequence of this, because we don't have a convenient laboratory test for endometriosis, many adolescents, teens and young women suffer for years with painful periods. And there's some evidence to suggest that diagnostic delay in this population may lead to worse prognosis in terms of pain and fertility outcomes. So, it's really incumbent upon the field of endometriosis investigators to find a more convenient and ready diagnosis for endometriosis. And in the meantime, the reality of not having a diagnostic marker for endometriosis highlights the importance of increasing awareness for the condition. So, it's a good thing that endometriosis is highly searched on Google because awareness is increasing about the condition.

In the absence of this test to diagnose endometriosis, the diagnosis is really made on the basis of a careful medical history and pelvic exam with attention to pain mapping. Imaging studies can also be useful, pelvic ultrasound in particular. And this is predominantly how I do physical exams, is through the pelvic ultrasound modality because it's also helpful in identifying ovarian endometriosis when present. Finally, MRI has proven useful as well for the detection of the deep infiltrating form of the disease.

The gold standard for endometriosis diagnosis remains surgery, typically in the form of laparoscopy. And when I'm working with residents in performing laparoscopy for endometriosis, I encourage a biopsy of representative lesions or excision of lesions so that a histopathologic confirmation of disease can be rendered. There are multiple studies that show that the surgeon's macroscopic impression, particularly of early stage disease, is not always accurate. So, histopathology is a really nice adjunct to the laparoscopic approach to disease.

Management of endometriosis, well, that's really contingent on the goals and the priorities of the patient. For those patients that prioritize fertility, laparoscopic surgery and/or fertility treatments are both evidence-based. I also manage quite a few patients who are presenting for the condition of endometriosis-associated pain and are not interested in fertility at the moment. And for those patients, I recommend a two-step approach. The first step is the treatment of existing disease. And this really highlights the importance of reducing the lesional burden. And you as a gynecologic oncologist know all about reducing or debunking lesional burden, and that's really important in endometriosis as well. It's typically performed via laparoscopic or robotic-assisted approach. Although there's some evidence that this can also be accomplished by a select hormonal approaches such as prolonged reduced estrogen states with a GnRH agonist, for instance. So treatment of existing disease, the first step.

The second step, and this is the step that's often overlooked in endometriosis management, is the prevention of recurrence. And the prevention of recurrence really is conducted by reducing or eliminating retrograde menstruation, which is the harbinger of new-onset disease. This can be accomplished using a variety of hormonal approaches, including oral contraceptive pills taken either cyclically or continuously, long-acting contraception options such as levonorgestrel-containing IUD, generate agonists such as leuprolide acetate, or the newer form of treatment with abundant evidence to support its use, is GnRH antagonists such as elagolix.

And importantly, the approach to endometriosis care can require multiple practitioners. And I think this is one of the messages I really want to leave with patients who may be listening to the pod, is that a multidisciplinary approach to endometriosis is really, really vital to improving outcomes of treatment. I'll give you an example. Pelvic floor physical therapy can be extremely beneficial for patients with chronic pelvic pain, dyspareunia or pain with intercourse or pelvic floor tension myalgia that can be associated with endometriosis. So having a coordinated care team is really, really critical to maximizing outcomes for pain patients.

Warner Huh, MD: Yeah. I want to highlight something that you mentioned at the end there, which is the multidisciplinary approach. And if there's anything that I have learned over the past several years is that women are best managed with endometriosis by a team. And that team will include the gynecologist, the infertility specialist, maybe even a pelvic surgeon, the pelvic floor therapist. And it's actually important for our listeners and patients to understand that because I think that's how we optimize outcomes for many of these women that have endometriosis.

So, that's kind of in a way the perfect segue for my next question to you, which is, and you briefly touched upon this, is what are some important considerations for an individual who has endometriosis and is trying to become pregnant? I know that that is a topic of great interest to all infertility specialists, including yourself, Dr. Burney, but I thought you might want to comment on that.

Richard Burney: Yeah, that's a great question. Thanks. You know, though I deal with a lot of patients that are presenting with endometriosis-associated pain, the majority of my practice is actually dealing with patients who are presenting due to an inability to conceive in the setting of endometriosis. So, this is near and dear to my practice.

There are a number of areas in which endometriosis has been demonstrated and negatively impact fertility, but the common denominator to most of the research that has been done in this area, is that pelvic inflammation is the etiologic factor in impaired fertility. So, you know, just reviewing the process of fertility, it's such an elegant sequence of steps from oocyte development, ovulation, ovum captured by the fallopian tube, fertilization, embryo transit to the uterus, and finally embryo implantation into a receptive endometrium. And studies have demonstrated chronic inflammation, a hallmark feature of endometriosis, can alter any or all of these steps in affected women. So, mitigating inflammation is really critical towards optimizing fertility success in patients with endometriosis.

I'll give you a few examples of how inflammation has impacted some of these steps. Cycle phase matched endometrial gene expression signatures in women with endometriosis are really different when compared to those of unaffected fertile women. Other studies have shown that estrogen actually fans the flames of inflammation or exacerbates inflammation in women with endometriosis. So, these molecular studies that have been done that have demonstrated the impact of inflammation really kind of guide our approach to this patient population when they're attempting to conceive.

There are some other important management considerations. There's an association of thyroid antibodies with endometriosis. So, screening for thyroid disorders in this population is recommended. There's evidence that reducing the burden of disease via laparoscopy for patients with early stage endometriosis results in higher pregnancy rates than no treatment at all. One of the larger surgery for fertility studies that have been published revealed this finding.

And then, finally, there's evidence that estrogen dependence of the condition and reduction of estrogen-associated inflammation can elevate the fertility of patients affected with this condition. So, we'll sometimes use GnRH agonists for disease suppression as it will lead into ovarian stimulation. And for patients undergoing IVF, freezing all the embryos and returning to transfer once the elevated estrogen levels have reduced to optimize pregnancy and minimize inflammation is a viable strategy.

Warner Huh, MD: Yeah, there's a lot up there. I mean, you know, I always knew that there was an association with endometriosis and fertility outcomes, but I actually learned something today about gene expression and, you know, just sort of the mechanistic association with endometriosis and infertility. So really, it's a fascinating answer to that question.

So again, you know, we're all super excited that you're here at UAB and that you've decided to come home after many, many years. I thought the listeners might be interested to know your thoughts on our services and care in your division and what you're already proud of, given that you've only been here for essentially a month and a half, and what you're most excited about in the future for infertility and reproductive endocrinology.

Richard Burney: Well, there's a lot to be excited about here at UAB. The connectedness of the divisions within the department is a source of excitement for me because there's that sense of connection and communication between the specialists and within OB-GYN. As far as the team of professionals in the Division of Fertility and Reproductive Health, I'm very excited about the quality of the professional staff. Front desk, medical assistants, technicians, nurses, embryologists, and the faculty all work as a team to provide compassionate, personalized patient care. And that's very evident to me even in the short two months that I've been here at UAB.

As far as programs are concerned, there's a lot of exciting developments within the division and department. The Fertility Preservation Program at UAB is a very successful one, very well connected among the oncologists at UAB as well as in the community. In collaboration with pediatric colleagues, in fact, the team has set conditions to add ovarian tissue freezing as a fertility preservation option that is particularly important for adolescent and young adult patients affected with cancer. So, a lot to be excited about with oncofertility and fertility preservation.

For our patients with infertility of uterine origin, the UAB Uterine Transplant Program is now a well established option. For patients like the Oncofertility Program, the uterine transplant program succeeds mostly because highly professional, highly coordinated, multidisciplinary approaches exist uniquely at centers like UAB. So, that's an emerging and growing program within the department and the division.

And finally, I'm excited about the infertility benefit for UAB employees. Not only for the tangible benefit in terms of the healthcare that will be delivered for those in need, but also for the significance of the university recognizing that infertility and early pregnancy loss are disease conditions that merit insurance coverage. And that's a huge step forward for our patient communities, not only here in Birmingham, but also in the greater state of Alabama. So, very excited about a lot that's happened here and and looking forward to promoting these programs and others in my time here.

Warner Huh, MD: No, that's a lot already. And I just kind of want to re-articulate some of the things that you're excited about, that I'm also excited about. For those of you that are interested in the Uterine Transplantation Program, I did a podcast with Dr. Paige Porrett who is the lead transplant surgeon for that program. So if you want to learn more, she does a great job articulating the specifics of why uterine transplantation is important to women.

And as you mentioned, Dr. Burney, I think the oncofertility program is amazing. And we've also had Dr. Sukhkamal Campbell on this podcast talk about that. And what she really didn't touch upon on that, but you did is this issue of ovarian tissue preservation. And I remember not so long ago that egg preservation was a big deal and now we're leapfrogging to ovarian tissue preservation. And it's just something I'm proud of because, you know, it's something that we're offering to our patients who are in need of that kind of service. And it's just not commonly provided. And I just want to credit you and your team for building out those clinical services.

And then lastly, the infertility benefit, you know, it's one of these things that I think it's important for the UAB community. I'm very much committed as you are to expanding that benefit so that it's truly meaningful for employees and couples who are trying to become pregnant. So, I think it's really important for individuals who work at UAB or associated with UAB.

And the last two things that I don't think that you touched upon, but you definitely need to give yourself credit for is, you know, I know that you have a significant interest in precision-based research in terms of outcomes. And so, I'm excited for some of that work that you will hopefully introduce in the near future.

And the last thing that we've already mentioned, and this is thematically something that comes up over and over again, is this multidisciplinary approach that we provide to care. And I think endometriosis is another great example of that. And, you know, even though you and I have just talked about it, I very much see this being implemented in the very near future, is creating really a true multi-D clinic of excellence in looking at how to best manage endometriosis patients. And so, that's something in the horizon that hopefully I'll invite you back, we could talk about that in another podcast. So, I don't know if you have any other closing thoughts or comments for the listeners today.

Richard Burney: No. I'm excited about what you just mentioned as well. I ran an endometriosis clinic for the military at Madigan, so appreciate the multidisciplinary approach that's required for that. And I would be excited to participate in a service for Alabama and Birmingham that focuses on endometriosis as well.

Warner Huh, MD: Great. Well, again, I want to thank Dr. Burney for discussing the topic of endometriosis as well as endometriosis-associated infertility. It's really fantastic for you to be a part of our department. And as always, please rate this podcast and we welcome any comments, particularly on topics that you're interested in learning or hearing more about.

And for more information on our infertility services, women's services, services related to , reproductive endocrinology, please check out uabmedicine.org. So until next time, thank you. Have a great day. We're not going to do a December podcast in celebration of the holidays and we'll kick this off again in January of 2023. Have a wonderful holiday. Take care. Peace out. Bye-bye.