A Podcast on Patient and Physician Perspectives on the Management of Endometriosis and Relugolix Combination Therapy

Endometriosis is a common disease which typically takes 7–10 years for patients to get a correct diagnosis; the delay in diagnosis can primarily be attributed to normalization of symptoms. Current treatment options include surgery, hormonal contraceptives, holistic options, and gonadotrophin-releasing hormone (GnRH) agonists. Oral GnRH antagonists suppress estrogen production, and are therefore limited to short-term therapy. Relugolix combination therapy combines a GnRH antagonist with low levels of estrogen and progestin, to protect the uterus and facilitate longer-term use. Ultimately, relugolix combination therapy may provide an alternative to long-term treatments, and could replace or reduce surgery in some patients. PODCAST VIDEO (MP4 206378 KB) PODCAST VIDEO (MP4 206378 KB)

This article is published with digital features, including a podcast to facilitate understanding of the article. To view digital features for this article, go to 10.6084/m9.figshare.26105251. A podcast on patient and physician perspectives on the management of endometriosis and relugolix combination therapy. Introducing podcasters. Dr Sanjay Agarwal, reproductive endocrinologist and director of the Center for Endometriosis Research and Treatment at the University of California, San Diego Center, and Tara Mangum, patient advocate and women’s health expert, supporting those battling endometriosis through their patients journey. Tara Mangum : Good morning, Dr Agarwal. It’s great to be here with you today. Could you tell us a little bit about what is endometriosis and who does it affect? Dr Sanjay Agarwal : Good morning, Tara. Nice to be with you, too. So endometriosis is a common disease, right? It affects about 5–10% of reproductively aged women [ 1 ]. And what it is, is the presence of the uterine lining outside the uterus. It’s commonly found on the ovaries, the bowel, the bladder. But it can also be found further afield, like, for example, in the lungs or in the skin [ 1 – 3 ]. The problems endometriosis causes largely include pain, pain with periods, is very common, pain with sexual functioning, pain at other times of the menstrual cycle, and also a decrease in fertility. So this is a common disease with what can be quite debilitating symptoms [ 4 , 5 ]. So Tara, you mentioned that you have endometriosis. Could you please describe for us endometriosis from the patient perspective? Tara Mangum : Sure. And I totally agree with the debilitating pain. So a patient journey is very trying and exhausting, as I’m sure you’re aware. Many first experience severe pain with their periods, but we’re told it’s a bad period and then a bad period is normal [ 6 ]. So we often compare ourselves to others and wonder why we can’t handle the pain the way they do. And then that causes us to sort of self-isolate. And then we don’t seek medical attention for years because it’s just been normalized. By the time we finally push ourselves to go see a doctor, we may receive a diagnosis. It maybe doesn’t sit right with us in our gut and we don’t feel it’s right, but we remain silent. And so we go back to suffering quietly and the cycle goes on for years. So the stigma around endo continues. And it takes, because of that cycle, it takes 7–10 years to get a correct diagnosis [ 6 – 8 ]. The consequences of the misdiagnosis are missing school, work, social events with our friends, and it continues to impact our quality of life [ 9 ]. We’re still battling the disease. There’s other impacts like infertility or worsening of the pathology and then possibly, you know, down the road organ damage or even pain centralization [ 10 ]. So my quick personal story I’ll share. I remember throughout high school since I was 14. Every single month during the first 2 or 3 days of my period, I would spend the day in the nurse’s office with a heating pad, you know, or ibuprofen. Nothing was helping and just sitting there in agony. And, you know, I’d see a handful of doctors, but they had all basically told me it was normal and I just wasn’t handling it as strong as others. So I just suffered for a long time. And even as I got into my late teens and early twenties, would almost get fired from jobs for missing time, you know, a couple of days a month because it literally couldn’t get up and go into work. So it wasn’t until I actually got married later on in life and tried to conceive when I saw a doctor who actually discovered a cyst and from there was properly diagnosed. So it just shows and supports that, you know, all this cycle and stigma and misinformation and misdiagnosis leads us to where the 7 to 10 years is still very much common for a proper diagnosis. And so sharing correct information is just essential to the disease. Getting diagnosed properly. But, you know, and we need to really make sure that we’re getting correct information so that we can decrease the time to diagnostic diagnosis and then improve the quality of life. So I shared that. Dr Agarwal, can you share how endometriosis is diagnosed? Dr Sanjay Agarwal : Tara, I think what you went through is so important. You know, this delay in diagnosis 7–10, 7–12 years is quite unacceptable for many, many, many reasons, isn’t it? And you talked about how pain is normalized on the patient side as well as unfortunately on the health care provider side [ 6 , 11 ]. And I think we’ve got to move away from that. Unfortunately, health care has failed our patients in this way, patients with endometriosis. And I hope going forward we can do better. The traditional way of diagnosing endometriosis has been surgical, and that is the gold standard to look for those ectopic implants of endometriosis [ 5 ]. But it’s not the only way. You know, the way I think of it is that there are three ways to diagnose endometriosis. We can diagnose it surgically, we can diagnose it with imaging such as I think in your case, when the cyst was found that highlighted the possibility of endometriosis; these days, ultrasound and MR are improving in sensitivity all the time, and these are great modalities to also diagnose endometriosis and also increasingly clinically diagnosing endometriosis clinically based on exam symptoms, clinical profile, because we understand that 70% to 80% of pelvic pain is endometriosis in the first place [ 12 , 13 ]. If we exclude other common causes, then it’s probably endometriosis. And our focus, of course, is to improve pain and improve quality of life. And we shouldn’t always require the patient to have a surgery before moving ahead with that mission. You know, the ultimate goal, I think, is to diagnose endometriosis early so that the life course or the life trajectory for that woman can be better, so she can study better, not miss school or college, she can hold down a job better, maintain relationships, better we can diagnose and effectively treat earlier. We have the chance of maximizing the life for that person in front of us. Yeah. Important point, Tara. So when a person has been diagnosed with endometriosis, eventually, what are the important things from their perspective to discuss with the health care provider, you know, in a shared manner? Tara Mangum : Yeah, absolutely. I loved one of the things you said where it’s like, you know, hey, we might not always need to jump straight to surgery because that’s one of the things I always encourage our community to think about is like when you first get diagnosed, what is important? First, take time to absorb it, you know, do research, but then make a list of what’s important to you. What is your goal? Obviously, most people’s goal would be to be pain free, but how do we get there? You know, some people want to avoid surgery where others may want to say, let’s go straight there and I just want to be done with it. Also, you know, are things like preserving fertility something that’s important? So I say make that list of what’s important to you and especially within your treatment plan, and then have that dialog with your physician. As you mentioned, shared decision-making was so important in developing a plan together. And if you are both in and engaged in acceptance of this plan, it’s much more likely to be successful. You know, sometimes there’s a multidisciplinary team of specialists required for my case. You know, I had GI [gastrointestinal] impacts, you know, I had urology impacts [ 14 , 15 ]. So engaging that, you know, and having that conversation with your physician and then even those physicians, you know, being in communication and working together. But even things like be sure you know what’s included within your insurance, there’s insurance considerations, right? Different policies cover different things, as I’m sure you see firsthand all the time. So, you know, collectively bringing that together and making a plan that works together is what we always suggest. And then lastly, like trust our guts, right? Not every relationship’s meant to be. Maybe there’s a chance where you don’t feel comfortable. It’s okay to feel that way, and it’s okay to get a second opinion. So those are sort of the things that are important to us from a patient perspective. So in talking with that doctor, what is the important part of discussing goals with patients from a physician’s perspective? Dr Sanjay Agarwal : Well, I think this is hugely important, you know, to establish the goals in a shared manner [ 15 ]. That way, we know what we’re aiming for and that we have a similar understanding; of course, it’s the goals of the patient that matter primarily. So I usually start off the conversation with new patients and say something along the lines of, you know, for most of my patients, I think we have about five goals. One is to improve pain, of course. But number two, we want to improve that pain in a way that it doesn’t adversely affect quality of life. It’s no good improving pain, but everything else falls apart in the process. So we care about the tolerability of treatments. Three, because of those improvements in pain and quality of life, we want to minimize ER [emergency room] visits. We’d like to reduce the use of opioids, narcotics, and we’d like to minimize the need for surgery. And I usually say something like, you know, these are the goals that we see for our patients, but are they consistent with your goals? Because really, it’s your goals that matter more than ours. And the vast majority of patients are aligned when they arrive with those goals. And I think they appreciate having a target that we are working towards with them. And I think that’s a very meaningful conversation. It’s well worth the time at that first visit, especially to just reinforce to the patient that we care about their goals we have some understanding of them. I think it’s a great way to start off a relationship because, of course, endometriosis is not a 10-minute disease or a 6-month disease or even a 6-year disease. It goes on for decades. And so there has to be good communication through this process. And it takes that to a collaborative communication to really, I think, get the best possible outcomes over time. Unfortunately, even today, about 70% of women that are diagnosed with endometriosis still live in pain [ 15 ]. So I think there’s a huge opportunity to do all of this much better. Tara Mangum : Thank you, doctor. You know, one of the things you just said really resonated with me was you want to reduce the ER visits while also reducing opioid use. And I think that’s something so important to our community. So in addition to what you just shared, what treatment options are available for patients battling endometriosis? Dr Sanjay Agarwal : Yeah, so it’s fine having goals, but the next step is, well, how do we actually achieve those goals? And so the way I tend to discuss this with the patients and, you know, my residents and fellows hear me say this time and time again to every patient, pretty much they’re probably getting bored. I say, you know, we have three groups of options to try and achieve those goals that we’ve talked about. Of course, we have surgery and that is important in many patients where nothing else works. So we appreciate the benefits that [surgery] can provide for some patients. But we’ll keep that aside and we will use that when nothing else works. And that’s consistent with the most recent global guidelines on endometriosis, the ESHRE guidelines, the Endometriosis Society for the European Society for Human Reproduction and Embryology, and they say keep surgery as a last resort [ 16 , 17 ]. So keeping them aside, then we have medical options and of course first-line options tend to be nonsteroidal and contraceptives [ 18 ]. And then the traditional more long-term sort of treatment, the more effective treatment has been GnRH [gonadotrophin-releasing hormone] agonists for the treatment of endometriosis [ 19 ]. These have often been depo preparations. And then we have complementary options. You know, there are data suggesting that nutrition, acupuncture, and pelvic physical therapy can sometimes help with pelvic pain [ 15 ]. And so we do utilize some of those more holistic options as well. I’m personally a huge believer that mental health matters and I find it totally bewildering how so many patients with a long journey with pain have not had this aspect of care discussed with them [ 15 ]. And so I don’t let anyone leave without at least discussing the topic of mental health. Many already are seeing someone, which is fantastic, but so many, the majority are not seeing someone for mental health, have not had that discussion, and pretty much almost break down in tears as someone’s actually understanding and discussing this. I think health care doesn’t do a good job with this for a variety of reasons, but I would urge people to please, please be proactive and talk to patients about it. They will appreciate it. I think that’s so important. So, Tara, we’ve discussed some of the, you know, unmet needs regarding endometriosis and perhaps you could please provide your experiences with regard to the important aspects of endometriosis care. Tara Mangum : Definitely. So you hit the nail on the head when you talked about the mental health aspect. It is a huge unmet need in our community [ 20 ]. It’s one of the biggest unmet needs. Honestly, the disease impacts us so much and like you said and alluded to earlier is it’s not talked about. No one asks us how we’re doing emotionally and mentally. There are so many burdens that come with this disease outside of the pain. There’s obviously the quality of life, but you have guilt because you’re not able to go to an event or you feel like you’re letting your family down. You have guilt from financial burdens. Relationship burdens for those unable to conceive; can you imagine the impact that has on a mental health rate? The quality of life just deteriorates and then you also start to feel hopeless when you’re not able to get the help that you need [ 21 ]. Unfortunately, in our community, the suicide rates are high among endo patients, and we’ve seen more and more suicides because I think... the people battling endometriosis cannot fathom thinking of spending years like this, many more years, or all the treatments or maybe not even having the money to get into a doctor and get the treatment that would be successful for them, you know, so mental health impacts are crucial and it’s a huge impact [ 22 ]. And you also have higher cost rates, right? [ 23 , 24 ]. All the medicines, all the treatments, if there’s surgery, recovery, you know, fertility treatment costs, all of those are just truly unmet needs in our community [ 6 , 25 ]. And one of the things I love that you’re saying is something doctors and physicians should focus on that I would love to see it much more in our community. So as I shared all of the unmet needs, you know, are there any new medications in this area that clinicians should know about? Anything that you can share, doctor? Dr Sanjay Agarwal : Yes, Tara, there are; you know, we talked about the need for tolerable options. The longest approval for the options we’ve had has been about a year. And so more recently we have a new class of agents that have been available to us. And these are the oral GnRH antagonists [ 26 ]. Prior options—the GnRH agonists—tended to more completely suppress estrogen production, leading to more adverse effects or hot flushes, bone loss, etc. And the goal of this new class of medicine is to have an option that’s, of course, firstly effective, but also with reduced side effects because, you know, tolerability matters. So Myfembree is one of those newer oral GnRH antagonists, and it’s actually a combination of relugolix, the antagonist, in combination with low levels of estrogen and progestin. The estrogen is natural estradiol at low levels, and the progestin is norethindrone acetate, which is required to protect the uterus when giving estrogen to prevent the endometrium from developing hyperplasia. Relugolix is a non-peptide GnRH antagonist that binds to the receptor and lowers circulating estrogen levels from the ovary. These are FDA [US Food and Drug Administration] approved for the treatment of endometriosis, so studied in large studies; and the main side effects from lowering estrogen can be bone loss and hot flushes [ 19 ]. These are the main focus of all the big studies looking at this aspect of medicine and the goal of that, as I mentioned, is to reduce these unwanted effects. In the European Union and the United Kingdom, this agent, called Myfembree in the USA, is also approved [ 19 ]. And there are also the studies that led to the approval, SPIRIT 1 and SPIRIT 2, which, you know, studied women in the appropriate age group, 18–50, and found that there was a good improvement in pain [ 27 ]. And these are studied for, you know, a good couple of years and clearly, they’re effective. Clearly, the side effects are reduced. For example, the impact on bone density is less than about 1%. So... that’s less than other agents basically that we’ve had in the past. Most of the patients, about 75% of the patients studied in these studies SPIRIT 1 and 2 had improvement in pain with periods, compared to about 30% of those taking placebo [ 27 ]. During the same time, 75% in the active groups are clearly much more effective than placebo. Also, around 60–65% in these studies had improvement in pain between periods—non-menstrual pelvic pain, we call it. In general, this is a hard pain to improve. It’s much easier to improve the pain of periods because we can shut down periods. But actually improving the pain between periods is more challenging. And so to have a 60% to 66% improvement in that compared to about 40% in placebo, that’s a big improvement. And welcome as well. Regarding tolerability and adverse events, the most common side effects were mild, but they included headache. Some pharyngitis and hot flushes. But all of these were in less than about 15% and not severe. I’ve mentioned the bone density loss minimal at 1%. So that was very nice to see. And it’s a major focus actually of the FDA. In addition, there are ongoing studies looking at the contraceptive aspects of Myfembree, relugolix combination therapy; currently... this is not approved for contraception and patients should use barrier contraception as necessary. But the ongoing studies—the SERENE studies—are looking at how well does this work as actually a contraceptive. So hopefully we’ll have those results at some stage soon. The medicine should be started, of course, during or soon after a period [ 28 ]. Make sure the patient’s not pregnant and in the USA there’s a 2-year approval. I should mention, while we’re talking about these new classes of agents, because there is a little bit of estrogen in Myfembree, it has the same black box warning as birth control pills, and every agent with estrogen like menopausal hormone therapy. And that is that it can lead to thromboembolic risk. So for those at risk of clots, [these agents are] probably not the best option. So it’s good to have newer effective options that are tolerated so that we can treat women in a more conservative, less invasive way. Tara Mangum : Thank you so much, Dr Agarwal, for sharing all that information that you just said. It’s incredibly great to see that the industry continues to try to advance medicine to help those of us battling endometriosis. So loved hearing about the new therapy options and really appreciate discussing today with you. Dr Sanjay Agarwal : And Tara, you know, as we’ve discussed, endometriosis needs so much more awareness and thank you so much for your work in highlighting this common but underrecognized disease and how devastating it can be and things that make a difference to the lives of women that are actually suffering from this disease and those around them. I think we need that very much. So thank you very much for joining us today. Thank you.

Below is the link to the electronic supplementary material. Supplementary file1 (PDF 284 kb) Supplementary file1 (PDF 284 kb)