Mauricio Abrão, MD

 Despite the recent advances in the treatment landscape, as we conclude our conversation, what would you say are the gaps that remain in the care of patients with uterine fibroids? How do you see that being addressed in the future?

 When we talk about the future, we should start with a better understanding of the physiopathology of fibroids. Because when we better understand the role of the extracellular matrix, the genetic options, and the interactions between oncogenes and the growth of the fibroid, we stop thinking about hormones to treat the disease and we’re going to treat the growth of the fibroids. This is the dream. This is the same as when we talk about the future of treating endometriosis. What we have now are hormonal treatments. In the future, by defining the genetic pathways, we may have solutions that may be even better because we’re not going to talk about adverse effects and things like this.

In the future, we may also have better tools to help with diagnosis. Look at the example of when we talk about laparoscopy to treat fibroids. It will also help us define the difference between fibroids and sarcomas. If we have a better pre-operative diagnosis defining precisely, “No, this isn’t a sarcoma,” you can do a treatment without being afraid of disseminating the tumor or things that are relevant. Options for robotic surgeries are growing a lot and may be part of this future. What do you think?

 I’m very passionate about where we are in research and the research dollars that go to women’s health. But also from an education standpoint, there are so many gaps in education that we need to do a better job at, whether that’s within the examination room, with what’s available for women to understand, and even with men understanding a women’s health issue. We know that age, income level, health insurance, and health care proactivity all impact the health outcomes that we see for all diseases. But specifically for fibroids, we know that women’s health conditions can have overlapping symptoms that women are unsure of and don’t realize may be devoted to a fibroid.

There’s also the negativity that we’ve seen in the past toward fibroid and fibroid health. We need to create more health equity when it comes to talking about this particular topic in general because it impacts more Black women than any other race, like we discussed. The real concern is how we reach a certain community within fibroids to get to the heart of why this is impacting women’s lives to such great numbers.

That sometimes comes down to genetics. If we were thinking of precision medicine and more from a genetic perspective on how we can impact the genetic foundation of fibroids through research, and therefore, maybe even get to a point where we see fewer fibroids overall, that would impact these outcomes and adverse effects that we’re talking about. But if we found a way to decrease fibroids in general from a genetic standpoint, then we wouldn’t necessarily have to place so much emphasis on the treatment of fibroids because we’ve impacted the actual disease state itself. Patient education, research, and increasing awareness is where we need to focus our efforts, just like you stated.

 I completely agree, Jessica. This is why the AAGL [American Association of Gynecologic Laparoscopists] is probably one of the main gynecological surgical societies worldwide. We just finalized our strategic planning thinking of the next years. One of the most important pillars is how much we’re going to invest in research and become more scientific for this society. The other one is the investment that we’re going to make on education. Education isn’t only to educate doctors, it’s to bring patients to the discussions and educate patients about the advocacy groups. It’s part of the present that we need to invest in a lot. This is one of the goals of this year, being the president of this society.

 I’m glad that you’re taking that initiative and that stand because it comes from a standpoint of leadership to help everyone else understand exactly what the agenda is and where we need to change the course when we think of women’s health. From our discussion, which I’m so delighted that I’ve been able to share this time with you, it’s clear that we have seen that being proactive with one’s health and overall wellness is key for understanding the disease state and what comes with that.

When we think from a uterine fibroid standpoint about fibroid symptoms and potential treatments, the core of what we should be focusing on is that mission to educate women about their bodies, uterine fibroids, and all the treatments that we’ve been able to discuss through this discussion. I’m very hopeful that this will help others learn about new technology and innovation and help counsel patients better. As a community of physicians and OB/GYNs, we can use these discussions to propel ourselves forward in our professions, our research, and in women’s lives.

® for this great initiative for us to do this 

 video program. Things like this are very helpful for us to disseminate the right information, as we’re doing here. It’s very nice to be with you here, Jessica. It was a great pleasure.

Videos

Mauricio Abrão, MD, and Jessica A. Shepherd, MD, MBA, FACOG, address gaps in care for the treatment of uterine fibroids and share the importance of patient education in disease management.

Unmet Needs in the Management of Uterine Fibroids

 There are some important things to consider because sometimes we need a more efficient antiestrogenic effect in the beginning and then we can transition to an add-back for this purpose. This is something that we must consider. Let me know your thoughts.

 I definitely think that we have more room to go, but having 2 on the market is significantly helpful for practitioners. And even outside of OB/GYNs, this allows mid-levels and family practitioners and internal medicine doctors who see these patients with heavy menstrual bleeding to allow them some impact in decision-making when it comes to how we can help our patients with their heavy menstrual bleeding. What would you say for those who are viewing, Mauricio? What recommendations do you have for colleagues on treatment selection and considerations for GnRH [gonadotropin-releasing hormone] antagonists in general?

 One thing to consider is the cost of the medication for patients who have insurance that doesn’t cover the medication. This is very relevant in Brazil because we participate in the trials but we don’t have this medication because of this issue. It’s the same in many countries all over the world. The situation is to define the criteria as you mentioned before, to discuss with the patients to check the cost of the medication to see if it’s affordable for them, and how much we’re going to use this medication. These are things related to the real world. Do you agree with me?

 I absolutely agree with you. As we start to use these agents more, we’ll start to see them decrease in prices. But it’s important for us as we’re going through that struggle with cost that we stay the course and make sure we still recommend and prescribe them so that they aren’t lost and patients continue having experience with them and being exposed to them.

Then there’s 1 more that has some investigational data within the UF [uterine fibroid] treatment spectrum called linzagolix. There are investigational data being done right now. But based on the data you’ve seen on it, how do you anticipate that this particular agent is going to fit into the treatment spectrum when we think of GnRH antagonists in medical management?

 This would be another option. When we have more options, it’s better for the patient. It’s another option in the spectrum of treatments. This may be part of the future options for the medical management of the fibroids. Do you agree with me?

 It’s good to have healthy competition within the state of things that we’re able to offer patients. That’s only going to push us forward when we think of research advancing this broad field of heavy menstrual bleeding and fibroids. It’s high time that women’s health has more options to offer because this is something that has been plaguing women’s lives for so long. We owe it to ourselves in the medical community, as well as in research, technology, and innovation to advance what we’re able to offer women.

Drs Jessica A. Shepherd and Mauricio Abrão share recommendations for the treatment selection of GnRH antagonists when treating patients with uterine fibroids.

Treatment Selection of GnRH Antagonists for Uterine Fibroids

 We can go in-depth about the individual agents that we have. We have a chance to participate in the trials of both elagolix [Orilissa] and relugolix [Orgovyx] for endometriosis. But I want to hear your thoughts, Jessica, about the indication of these agents for fibroids.

 You named the 2 FDA [Food and Drug Administration]-approved GnRH [gonadotropin-releasing hormone] antagonists, elagolix and relugolix, and how they’re able to rapidly have a reversible suppression of your ovarian sex hormones. The primary outcomes for both studies were looking at reducing fibroid-associated heavy bleeding. I’ll start out with elagolix. Both studies were looking at women who underwent randomized places, but the criteria was the important part.

This was a study looking from a medication standpoint on something that in the past we’ve typically used from a contraceptive standpoint. The primary end point was bleeding decrease over the course of time that they were in the studies, as well as having less than 80 mL, which we typically use as our clinical criterium for menorrhagia, and looking at patients who met both of those criteria. That was important. Because when we think of patients who come in with heavy bleeding, there are different parameters as far as how much you bleed vs how much bleeding we’re going to be able to decrease over time. It was hard for us to make that judgment using hormonal contraceptives and birth control methods in the past because it wasn’t necessarily made for that.

In addition to what we discussed before from a GnRH agonist standpoint is the hyperestrogenic effect that these medications have. Patients aren’t going to have as significant adverse effects as they experienced in the past. This is groundbreaking for patients as far as how we’re able to integrate both of these individual agents. Looking at the safety and efficacy from the [Elaris] UF-1 and UF-2 trials of elagolix, there was a significant reduction in heavy menstrual bleeding.

When we look at the adverse effect profile, from a safety and efficacy standpoint, patients who were in UF-1 and UF-2 didn’t have a significant amount of safety profiles that I would be concerned about in order to recommend that for my patient. This is allowing us to have even more tools in our toolbox when patients come in with heavy menstrual bleeding. This is where our research needs to be taking us, where we have more impactful medications that are going to give us medical therapies for our patients that have quick onset.

I’ve had real-world observations by using these agents in my practice. For example, early on during the pandemic, surgery was decreased significantly because ORs [operating rooms] were closed for elective procedures and being able to put patients on this medication in order to get them to a point where they would need surgery. I’ve even had patients who had such a significant impact of the decrease in their bleeding that they were like, “This is going to be my method of choice for what I’d like to choose for myself for an option for decreasing heavy bleeding.” That was one of the things where I want to get with patient care and offer many options and have patients be able to choose what’s best for them and their journey. This is where we’re starting to go and hopefully even getting better at it.

To contrast that with relugolix, what was the significance of that being evaluated when we have a combination of estradiol 1 mg and norethindrone acetate 0.5 mg in the LIBERTY trials? What did you see throughout those trials that you felt were impactful for patients as far as primary outcomes and even adverse effects?

 There’s an improvement of the adverse effects, but I don’t know if we can call these effects caused by the GnRH antagonist adverse effects because they’re effects of the reduction of the estrogens. These effects that we’re talking about, including hot flashes, occur because we bring the patient to the menopause status. When we add estradiol and norethindrone acetate, the reduction of the adverse effects is enormous. It doesn’t seem to reduce the effect of the medication in terms of the treatment of the fibroids. This is a good option as well. Mainly when we talk about reduction of the bleeding and the pain as well, this is an important thing that we must consider for both relugolix and elagolix.

Jessica A. Shepherd, MD, MBA, FACOG, and Mauricio Abrão, MD, assess the use of FDA-approved GnRH antagonists in clinical practice.

Safety and Efficacy of GnRH Antagonists in Uterine Fibroid Treatment

 It’s time for us to jump to GnRH [gonadotropin-releasing hormone] agonists and antagonists. This is something that we should discuss a little deeper because it’s a very contemporary issue with the antagonists that are coming. I’d like to start with the history of GnRH agonists, because after the substitution of 2 amino acids of the GnRH analogues, creating the GnRH analogues in the 1980s, a Nobel Prize was given to the developer of this medication. They created a new concept of the inhibition of the estrogens and it became a treatment for the estrogen-dependent disease.

The only issue that was considered from the beginning is that most of the GnRH agonists had a flare-up in the first 10 to 15 days that may have a negative impact for estrogen-dependent diseases. Also, the monthly use of the medication, or even the use of every 3 months, was a limitation that led the researchers to think about the concept of the antagonist. What can you tell us about the current availability of the GnRH antagonists, Jessica? Let me know your thoughts.

 Mauricio, I’m glad to see this as a part of progression when we think of clinical medicine, because like you stated, GnRH agonists, which obviously are different from GnRH antagonists, were a way for us to do deal with patients’ bleeding and fibroids. However, there were some adverse effects that weren’t necessarily as beneficial for the patient who experienced them. We’re moving into a day and age where GnRH antagonists are proving that we can see a rapid onset of estrogen suppression, but not to a point where it’s so hypoestrogenic that patients are having a significant impact in the adverse effect profile.

We’re also allowing patients to have something with an oral administration, which allows patients to feel that they have maybe a little more control or buy-in into the root of administration at which they’re going to impact their quality of life. The root of administration improves the experience for patients when we think of how they’re able to access and take their medication. From a GnRH antagonist standpoint, I have found in my practice that this is a way that patients can have some quick onset and significant ways of approaching how they’re able to address their fibroid symptoms from knowing newer technology.

Many of my patients who come in have either failed a form of medical management or are averse to it from stories that they’ve heard from friends, family, and relatives. Sometimes from a clinician standpoint, it’s hard for patients to understand that what someone else may have gone through may not necessarily be their experience. But now that we’re able to actually show them some new data and approaches to fibroid management when it comes to bleeding, that’s profound. We’re in a day and age where we’re starting to see that we have more to offer in this disease state of fibroids and heavy bleeding, when we may have only had 1 or 2 tools in our toolbox in the past.

This allows progression of conversation and the relationship with patients with their clinician, but also in making sure that we’re responsible from our end of discussing what that does from an estrogen standpoint, how that decreases, and the therapeutic efficacy that they’re going to achieve by taking these medications. It’s putting fertility back into the conversation early. Many patients want to know how this is going to affect their fertility. Mauricio, from the GnRH antagonist options that we currently have approved, how do you figure out who’s going to be an ideal candidate for a GnRH antagonist? What considerations do you consider when you’re starting someone on these newer agents?

 One of the things to be considered is when we talk about the flare-up. Because when we have a patient with heavy bleeding, if you do something like an antagonist, you’re going to have a flare-up and there will be an increase of the estrogen levels for these patients. This may be bad for the symptoms of the patient who’s looking for something to treat the problem. But when we give something that may be oral and the decrease of the levels of estrogen is very rapid, this configurate, one of the characteristics of the ideal indications for this [INAUDIBLE].

Another thing is that if the flare-up is important, when you stop the medication, such as when the patient wants to be pregnant, we can go back to the normal levels of hormones faster than in other situations. This can be an important indication for this. We’re talking about this treatment for the symptoms, but we need to consider this treatment as well when we think about big fibroids, reducing the volume of the fibroids to do a surgery or even to decide about another therapeutic option, followed by a clinical treatment before. Always follow it by a good imaging method for us to define this strategy for this proposal. These are good candidates. Looking for the volume of the uterus, the definition, the number of fibroids, the position of the fibroids, and the type of fibroids—submucosal, subserosal, or intramural—are important aspects to be discussed.

Experts in gynecology provide an overview of GnRH antagonists and examine the therapeutic use of these agents in treating patients with uterine fibroids.

Role of GnRH Antagonists for Uterine Fibroid Management

 Let’s move ahead and discuss the clinical options, Jessica. Tell me your thoughts about the role of estrogen and progesterone for fibroids, mainly because with the concepts related to the resistance to progesterone and the impact of progesterone in this trauma of the uterus, we need to think twice before deciding the medical treatment. Tell me your thoughts about this.

 Absolutely. We’ve had so much expansion when we think of progesterone and its effect on fibroids. There’s progesterone as far as promoting growth of uterine fibroids and increasing the proliferation in cellular hypertrophy. How we look at the actual extracellular matrix of fibroids and knowing the progestin impact on that is an important part of how we might recommend progesterones from a medical management standpoint. Then also understanding that it can be a combination. We can have a combination of medical management with some procedures that can allow longevity when we think of the patient’s ideal of what they’re looking for from me, being from a bleeding perspective or a mass perspective from a bulk symptom.

Uterine fibroids being a common benign tumor, we still need to look at reliable long-term treatments that are available for patients. How do we explain that to patients? In the past, we have done the best that we can, when we think back to the 1940s and 1950s, with the advent of birth control pills and knowing that they were able to help with bleeding and how we were able to manipulate the hormonal impact. Now that we have progressed into having more of a progestin impact from a birth control or contraceptive standpoint, we still need to make sure that we’re understanding exactly how that has a cascade of events that lead to excessive extracellular matrix deposition from a progestin standpoint.

Understanding patients when they come with a preceding medical management that maybe they’ve failed is digging deep into what they’ve taken, how it has failed them, and then making sure we’re using our clinical judgment to understand that there may have been some hormonal effect and what we should stay clear of from that particular patient’s experience. With patients who haven’t experienced certain medical managements, we can use our clinical judgment and expertise to present that to the patient as a possible option for managing their periods and their bleeding from a fibroid.

 Jessica, you mentioned something that needs to be reinforced, that progesterones can stimulate the cell proliferation and the accumulation of the extracellular metrics, which can promote the development of the fibroids. There are some studies that very clearly show that a high dose of medroxyprogesterone acetate may even increase the growth of the fibroids, and we need to think twice before recommending these kinds of medications to patients. Even the intrauterine devices with progesterone may have this relation.

You gave a very nice summary looking for the indications of this combination of estrogens and progesterones for fibroids as a clinical management. Let me know your thoughts about SERMS [selective estrogen receptor modulators] in terms of these agents and if they could play in the treatment of the fibroids.

 Typically, when we think of medications, we’re looking for things from the past that are going to manipulate the hormones to decrease bleeding. That’s usually when we think of contraceptives. But when we think of treatment of fibroids in a way that can potentially decrease the size of the fibroid without provoking a menopausal or a hypoestrogenic state, and also not creating more growth, like we were discussing with the progestin effect on the fibroid.

We have room for studies to look at how selective estrogen receptor modulators can reduce the size of fibroids and therefore impact the clinical symptoms that patients are having. We need more research. A fundamental standpoint that we should take during this discussion is that we need more research when we think of fibroids and their growth because there’s a large portion of fibroid growth that comes from a hormone-dependent standpoint. We may not know all of that at this time. We need more research that’s going to allow us to have a better manipulation or involvement of fibroids when we think of their growth patterns, their impact from a bleeding standpoint, and also how we can use medications, which we’ll get to when we talk about GnRH [gonadotropin-releasing hormone] antagonists, and how we can decrease the size of a fibroid and decrease additional growth.

These are tumors that have a propensity to grow in size like we’ve seen in many women who have significant growth in fibroids. But how do we impact in the way that’s going to improve quality-of-life factors and also improve it from a bleeding standpoint and even from a size standpoint? My summary would be that SERMS have some usefulness in the treatment of fibroids from a symptomatology standpoint. Then also, like you said, bringing that fertility aspect into the conversation as well. We have some good starting evidence, but we need to establish that more when we think of the benefit of SERMS in fibroid growth and quality of life. But we’re getting there, and I’m optimistic that we’re going to have even more to offer our patients in the upcoming years.

 I’m sure about that. But we also can’t forget the nonhormonal medical treatment for the disease because we have options like tranexamic acid for bleeding or even the nonsteroidal anti-inflammatory drugs that can reverse the relation with prostaglandins and create and reduce the bleedings associated with fibroids. Sometimes giving these medications is an additional option for this.

Drs Mauricio Abrão and Jessica A. Shepherd provide insight on treating fibroids with nonsurgical treatment options for patients.

Approaching the Medical Management of Uterine Fibroids

 This is a good moment for us to discuss surgical options.

That’s what you and I love. As minimally invasive gynecologists, we love surgical options, while understanding that there are medical options for patients. Historically, when we’ve seen fibroids, from a bleeding or even bulk standpoint, surgical options usually come into the algorithm of treatment options for patients. For both of us, our ideal options for patients may consider or include some surgical treatment. What would you consider for surgical treatment options? What do you think about the evolvement of expanding nonsurgical treatment options in that landscape?

 As you mentioned, we love surgery, but there is a concept that the best surgeon is one who knows when to not indicate surgery as well. This is very relevant for my patients and me in daily practice. One thing we should consider when we talk about the surgical indication is that, first, we need to think about infertility in patients, because most of these patients want to be pregnant or don’t have kids. Things like that should be the starting point for us as we think about the clinical and therapeutic options.

There’s another thing we consider when we talk about imaging. We work a lot with imaging in Brazil. We’re expanding the concept of imaging for endometriosis and many other things. When we talk about imaging, we calculate the volume of the uterus. That’s not something that all sonographers tend to do. The normal volume of the uterus is between 30 and 90 cc, and the turning point for us to start thinking about surgery—just talking about volume of the uterus—is more than 300 cc. That’s relevant for us to start thinking about, because when the volume is high, the uterus compresses other structures in the pelvis, and it’s additional factors for us to think about the impact on the quality of life.

The third thing is the presence of submucosal fibroids, because submucosal fibroids may be more associated with bleeding. In my opinion, it may also create more difficulty for the patient to get pregnant. One colleague compared the presence of submucosal fibroids with an IUD [intrauterine device] in terms of creating difficulties for the patient to get pregnant. When we combine the symptoms, the amount of bleeding, and the desire of the patient to be pregnant—all these aspects—we’re ready to define. With a volume of more than 300 cc, bleeding, and submucosal fibroids, we’re going to decide to do the surgical treatment. The type of surgical treatment depends on the future pregnancies the patient may have. What do you think about these ideas?

I love those ideas. I love that imaging plays an important part on how to stratify your patient. Fertility is something that over the last few years is becoming an important part of how we counsel patients. In the past, we didn’t pay as much attention to fertility in the discussion. That’s not to say that everyone has this abounding desire to have children. For women who don’t want children, that’s completely fine as well. It doesn’t mean that every woman wants to have a child, but we need to put that into the conversation much earlier than we were in the beginning.

I’m glad you brought up submucosal fibroids. When we think of the location of fibroid, there are many things about a submucosal fibroid that can change the algorithm or how we have a discussion about management with patients. From a fertility standpoint, it’s an impeding factor to fertility. But it also affects bleeding. In terms of location, we typically see that patients have more bleeding with submucosal fibroids.

One thing I love about submucosal fibroids, if I were to say anything about loving a fibroid, is that the location allows for a lot of minimal invasive procedures from a hysteroscopic standpoint. We’re seeing the advent or broadening of the platform on radiofrequency treatment of fibroids as well from a submucosal standpoint. Submucosal fibroids bring fertility into this category, but when it comes to management, patients can have big outcomes as far as decrease in bleeding, improvement in infertility, and a minimally invasive approach from a hysteroscopic standpoint that allow fibroids to be dealt with in a very concise and effective manner that allow patients to go on with their daily life very quickly.

We have evolved substantially when we think of surgical treatments or minimally invasive surgical treatments and even nonsurgical treatment landscapes. In your practice, when we think of surgical options, and now even blending medical management into fibroids, how has that evolved in your practice, Mauricio?

 You mean the decision between both strategies?

 Before jumping to this point, I’d like to remind everybody that something very relevant as well is the association between fibroids and adenomyosis.

Going back to the discussion about the importance of the imaging, sometimes when there’s an association between both situations, we need to consider this for this purpose. We have to consider these aspects that I mentioned for us to move ahead and make the decision about surgery and clinical treatment. When we talk about surgery, we need to consider myomectomies and the possibility of doing hysterectomies if the patient doesn’t have the desire to be pregnant in the future. Depending on the volume of the uterus, all these approaches tend to be minimally invasive. Nowadays, not thinking minimally invasively isn’t good for the patients. As specialists, we need to think a lot about this. But we have some clinical options to be considered that we should discuss. There are medical options to manage the fibroids, starting with the combination between estrogen and progesterone, progesterone alone, and other aspects.

Dr Mauricio Abrão leads a discussion on considerations for selecting the optimal surgical options for patients with uterine fibroids.