Dr Taylor is Chair and Anita O’Keefe Professor of Obstetrics, Gynecology and Reproductive Sciences and Professor of Molecular, Cellular, and Developmental Biology, Yale School of Medicine, New Haven, Connecticut.

Hugh Taylor, MD

There are still gaps in the treatment of endometriosis. One is we don’t have drugs that can be used to enhance fertility in patients with endometriosis. I hope we develop those. Those will probably be nonhormonal because altering reproductive hormones, which are necessary for pregnancy, is not a way to treat infertility. Understanding the basic pathophysiology of the disease has given us many clues and targets to pursue that may be good treatments for endometriosis that won’t alter hormone levels and will allow conception. We’re working on some of those in the laboratory. I think that’s one of the key things that we need to develop with these nonhormonal treatments that’ll be useful in endometriosis-related infertility.

I think the other gap is in diagnosis. We’re pretty good at diagnosing endometriosis clinically, and we just really need to be thoughtful and proactive about doing that, but diagnostic tests other than laparoscopy will be very helpful in making that early diagnosis, allowing for screening for endometriosis. There are several biomarkers under development now. I think we will have an endometriosis blood test within a few years that will make this diagnostic process much easier. Right now, cyclic progressive pelvic pain is typically endometriosis. I think we just need to be more proactive about making a clinical diagnosis and treating these women and not allowing them to go through years of pain before they get treatment.

The other thing that we need is more awareness. The women who are experiencing pelvic pain need to know this is not normal, not to have it dismissed, to know that there are treatments available. They need to feel empowered to speak up. We need to make sure that health care providers are aware of the disease, the clinical symptoms of the disease and the various treatment options available. I hope that people come away from this presentation thinking the patient with that cyclic pain, and that's the key, endometriosis pain is cyclic in character, varies with the menstrual cycle, and tends to progress over time. A woman with cyclic progressive pelvic pain most likely has endometriosis and should begin empiric medical therapy.

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Hugh Taylor, MD, provides insight on remaining gaps in care in the endometriosis treatment landscape.

Unmet Needs in Endometriosis Treatment

Most importantly, it’s the patient with presumed endometriosis, where we’ve made a clinical diagnosis of endometriosis. Somebody has that cyclic progressive pelvic pain, we think it’s endometriosis, we’ve ruled out other significant causes of pelvic pain, we don’t necessarily feel endometriosis on an examination, we don’t see it on an ultrasound, but the history is classic. I am very proactive in making a clinical diagnosis. The delay in treatment is so long right now. We’ve gone way too far to the side of missing diagnosis, harming patients because of this long delay, having them live years with inadequate or no treatment. I tend to be very aggressive at making a clinical diagnosis of presumed endometriosis and begin therapy. It’s gotten easier as our therapies have gotten easier.

Oral contraceptives were always easy and often we do that. We may not have made the diagnosis of endometriosis. We may have said it’s dysmenorrhea, light menses, and we’d start on our oral contraceptive. I’d make that clinical diagnosis of endometriosis. I’d let the patient know that is our working diagnosis, and I think it makes them feel much more heard, makes them feel like we are a true partner in treating this condition seriously. It allows us to go on to the next level of therapy if the pain is not relieved. I start with an oral contraceptive. If they have side effects or it doesn’t work, I'll move to a GnRH [gonadotropin-releasing hormone] antagonist. If they’re willing, I will often use the oral contraceptive in a continuous fashion. Most oral contraceptives are designed to be 3 weeks of active treatment and 1 week off to induce menses. If somebody has dysmenorrhea, why have menses at all? If menses are what are flowing in a retrograde fashion and feeding the endometriosis again, why have menses at all? When I can, I like continuous oral contraceptives to block menses entirely and eliminate that pain and potentially eliminate progression of disease or new lesions from forming.

I’m also not hesitant to go to a GnRH antagonist. When we just had the GnRH agonists as our next line of therapy or danazol, these are agents that had significant side effects. Most young women don’t want to take the risk of androgen therapy that may cause hair growth and acne, so danazol has not been a very popular treatment. When we had GnRH agonists as our treatment, where we had to give the patient an injection, knowing that it’ll have this flare effect where the disease would get worse for a week or 2 before it started to get better, knowing that this was irreversible at least for some time because of the slow-release depot formulation. Knowing that there were significant side effect, that it was this all- or- nothing response, we had to drop estrogen levels down to near zero—knowing all of these things, these were harder drugs to use and we wanted to be absolutely certain of our diagnosis and that would sometimes lead to doing laparoscopy just for diagnosis. I don’t do laparoscopy for diagnosis. I will make a clinical diagnosis.

We know that an oral contraceptive is effective in many women, but for those where the oral contraceptive is not effective we now have available the GnRH antagonists. These are oral, easy-to-use medication, act rapidly, can be reversed almost immediately, and where we can titrate the dose to get just the level of estrogen suppression to eliminate the pain often without the profound side effects. We can also give them with add-back therapy to eliminate vasomotor symptoms or other side effects if someone’s experiencing those, but given the ease of use of this medication, I think we can now make a clinical diagnosis of presumed endometriosis much more readily. We have more drugs in our armamentarium that make this easy to treat without the sort of profound commitment that we made when going on a GnRH agonist in the past. We wanted to make sure our diagnosis was 100% accurate. These days it’s much easier to treat with much milder patient-friendly medications with GnRH antagonists. It’s much easier to make that clinical diagnosis. We have to move the needle back on this to not wait 10 years from when someone has significant cyclic pelvic pain to the point where we relieve that pain with a definitive treatment. The field is moving toward clinical diagnosis and empiric early treatment, and I think that’s helping a lot of women.

Dr Hugh Taylor discusses his treatment approach for patients with presumed endometriosis.

Approaching Treatment of Presumed Endometriosis

There are many treatments available now. Thankfully we have some great options. The treatment landscape has expanded in the past few years, largely because of the introduction of GnRH [gonadotropin-releasing hormone] antagonists. There are many treatments available: oral contraceptives, progestins, the GnRH antagonists, the GnRH agonists, the old-fashioned danazol and androgen therapy, and surgical therapy. There are many treatment options available and shared decision-making with the patient is crucial.

Several patient populations are affected by endometriosis. One population is those patients with endometriosis-related infertility. Unfortunately, we do not have any medical therapies that improve fertility in patients with endometriosis.There is research ongoing to develop medications that will improve endometriosis-related infertility or allow us to alleviate pain while a woman is trying to get pregnant. But for infertility, women must come off the treatments for endometriosis. There are some data that pretreatment prior to an IVF [in vitro fertilization] cycle may be helpful in women with infertility as a medical therapy. We’re doing a large, randomized trial on that right now but short of in the setting of IVF, most of the things we do for endometriosis therapy cannot be used in women trying to conceive. Certainly oral contraceptives would prevent pregnancy and all the other drugs are not conducive to attempting to become pregnant. What we do traditionally is use some standard infertility treatments. We can think about using ovulation induction with intrauterine insemination. That improves pregnancy rates a bit. We can think about using IVF, which is very good at overcoming endometriosis-related infertility. Most women with infertility due to endometriosis will not be completely sterile and may be able to get pregnant without IVF. But certainly IVF gives them their highest pregnancy rate and is something you should consider if someone is a year without spontaneous pregnancy or even a shorter period for those over the age of 35 years who’ve been trying for 6 months. IVF should be part of the discussion and it may be worthwhile to have them see a reproductive endocrinologist.

Surgery is also an option. Surgery does improve fertility, but only by a small amount. It takes about 12 surgeries to get 1 pregnancy. I generally don’t recommend surgery to improve fertility. If someone’s having severe pain and wants their pain treated simultaneously with improvements in their fertility—maybe they’re in such severe pain that they can’t have intercourse and attempt to conceive—then sometimes surgery is the answer. However, the success rate per cycle of IVF is so much higher than the added improvement from a surgery that if pain is an issue, if it’s just endometriosis-related infertility, I would recommend traditional infertility therapies including IVF and referral to a reproductive endocrinologist.

In terms of patients with an endometrioma, it’s important to make sure it really is an endometrioma. That is the classic ultrasound ground-glass appearance. We can make a fairly confident diagnosis of endometrioma. If we’re not sure about the diagnosis, if it doesn’t have that classic appearance, if there are septations or fluid collections, that’s something you may really want to consider a surgical approach for to be certain that it is not a tumor or some other cystic structure. But most of the time we can tell that it’s endometrioma by that classic [ground-glass] appearance, something that’s persistent over several cycles.

It’s important to remember that the endometrioma will not necessarily shrink when you’ve suppressed the endometriosis. I use medical therapy initially for endometriomas and that may be an oral contraceptive or it may be a GnRH antagonist. The endometrioma is mostly composed of debris and old blood. That “chocolate-filled cyst” has old menstrual debris and blood. The endometriosis that’s the active grown lesion is really just the lining of that cyst wall. Even when we suppress the endometriosis—when that endometriosis itself that is the lining of that cyst wall has become dormant, inactive, fully suppressed by one of our medical therapies—the cyst fluid doesn’t go away. So I don’t expect to see shrinkage of an endometrioma and do not use that to gauge the success of my treatment. I will expect to see resolution of pain. In no one we see in endometrioma there are likely the other lesions throughout the pelvis that are probably more likely the source of the pain. Pain is probably a better indicator of the success of your treatment. Again, I don’t expect to see the endometrioma go away.

Deep endometriosis or deep infiltrating endometriosis is also more aggressive, more stubborn, more likely to be causing pain, and more severe pain. Those lesions I like to treat more aggressively. I will still start with medical therapy. These may be more likely to be resistant to progestin-based therapy. In those patients with deep endometriosis and very severe pain, sometimes I will skip an oral contraceptive and go right to a GnRH antagonist and if associated with very severe pain, in particular dyspareunia, I may even go to a higher dose of the GnRH antagonist. I think these are patients who need to be treated aggressively. When there is deep infiltrating endometriosis, it’s important that if we do progress to surgery, that that surgery will be done by deep excision. We have to be sure you’re prepared to do more aggressive surgery and be prepared for any eventuality. Those deep endometriosis cases should really only be done by those who are comfortable with that deeper section of endometriosis, full excision, rather than ablation of endometriosis.

I think we often will see effects of endometriosis on nonreproductive organs. Some of our studies have shown clear-cut effects on the brain that leads to that depression, anxiety, and pain sensitization. On weight, we know women on average with endometriosis are thinner than women without endometriosis, and there are metabolic effects that endometriosis has on the liver and on adipose tissue. Recently, we’ve shown even an effect on blood vessels and systemic inflammation. It may cause some damage in the long run. There are a lot of nonreproductive effects. Medical therapy will take care of all of the systemic effects of endometriosis rather than just the lesions in the pelvis so it’s important to get those women on medical therapy, not only to control their pain but also to control some of these nonreproductive effects. Sometimes we see actual lesions in the lung, in the brain. Cyclic hemoptysis or cyclic pneumothorax seen at the time of menses occasionally is evidence that someone has endometriosis in a nonreproductive organ. Again, before we go into surgical treatment of these nonreproductive organs, it’s always better to try this medical therapy to control this. I tend to be a little more aggressive if someone is having a pneumothorax, for example, or endometriosis in the lung than I would be for other reasons where they may have some very serious, life-threatening health complications. I may opt for more aggressive medical therapy, jumping right to a GnRH antagonist or occasionally even an agonist in somebody who wants that complete suppression and doesn’t want to take any chances with another pneumothorax after having experienced that and who may have some compromised lung function. You don’t want to risk that they’ll forget a pill or miss a treatment or otherwise be potentially exposed to another catastrophic event like that so I’m much more aggressive with therapy when I think there are lesions causing real harm to nonreproductive organs.

An expert in reproductive endocrinology reviews endometriosis treatment options for various patient populations, including patients with infertility, endometriomas, deep endometriosis, and effects on nonreproductive organs.

Treating Special Patient Populations With Endometriosis

Endometriosis can have a tremendous impact on quality of life. The pain itself can be debilitating. These women are often affected at critical points in their lives, during their education or early career. If they’re missing days of school or work, it may hold them back. This has a tremendous effect on their long-term career potential. These are things you just can’t make up sometimes. A lot of these young women are hesitant to participate in sports, theater, or other events at school because they never know when they’re going to be crippled by pain. That prevents them from living a full life. The pain itself is debilitating, and there are so many other symptoms of endometriosis that we know are caused by the disease, for example, the increase in anxiety, increase in depression, increase in pain sensitization that all dramatically affect somebody’s quality of life. Endometriosis can be a huge burden. It is far more than just some painful periods. It can affect somebody’s entire life trajectory. It’s important that we talk to them about this, that we recognize it, that we are open to discussing it with the patient and that we do whatever we can early, before there’s been some harm that may be hard to reverse. Again, if you don’t excel in school, it may limit your career options for your entire life. This has a tremendous burden on quality of life and life potential. We need to recognize it and think about early intervention.

It’s important for them to understand the totality of this disease on their lives. The bowel symptoms may be directly attributable to endometriosis, the bladder symptoms. As we just discussed, the depression, the anxiety may be related to and caused by the endometriosis. How this affects someone’s life can’t be overemphasized. I talk to my patients about recognizing this early, recognizing it with a clinical diagnosis, not waiting until it becomes so debilitating that they need a laparoscopy, trying to head it off early, trying to shorten that 10-year delay between the time someone has symptoms until the time they are given a diagnosis and definitive treatment.

An expert in reproductive endocrinology comments on the impact of endometriosis on a patient’s quality of life.

Burden of Endometriosis

There are terrible delays in our diagnosis of endometriosis today. It’s an average worldwide of 7 to 10 years between the time someone has symptoms associated with endometriosis and the time they receive that definitive diagnosis and get treatment. I think we can do better than this. I think early recognition is the key, awareness. This is a very hard thing for some people to talk about. Some of our patients are hesitant to talk about painful menses, painful intercourse, painful bowel movements, painful urination, which are all associated with endometriosis, but it’s important we ask our patients about this and be very open to hearing it. The other thing that’s hard to know is how painful periods can be considered endometriosis. The pain of menstrual cramps is really the only pain we as human beings have that we accept as normal. No other pain is considered something normal that we should accept. When someone first complains of dysmenorrhea, so often the response they get is, “Well menses are supposed to hurt, of course they hurt, just sort of toughen up or take a Motrin (ibuprofen).”

How do you know if your pain really is a lot more than what other people are experiencing? It’s very subjective. I think one of the first things we need to do to diagnose this early is to take this very seriously. Far too often it’s dismissed. I think we need to increase awareness about the disease so that people aren’t afraid to question whether their menstrual pain is abnormal. Often it gets to the point where it’s debilitating, where someone’s missing days of school or work before it gets recognized as abnormal pain. We need to have better ways to let people express their concern about dysmenorrhea and get them in for evaluation and treatment sooner. The other thing I think we need to do is start thinking about clinically diagnosing endometriosis. If someone has cyclic progressive pelvic pain, most likely that’s endometriosis. Rule out some of the other etiologies for pelvic pain, but most of the time that’s endometriosis. We may not feel any endometriosis on examination, we may not see it on imaging, but there’s nothing wrong with making that clinical empiric diagnosis and start thinking about treatment.

Endometriosis imaging has improved quite a bit. We’ve always been able to see endometriomas on ultrasound. I think one of the most important tools in diagnosing endometriosis is using ultrasound to rule out other potential causes of pelvic pain. Still, the vast majority of endometriosis we cannot see with imaging techniques. Superficial peritoneal endometriosis isn’t seen on ultrasound, it isn’t seen on MRI [magnetic resonance imaging], it is very hard to diagnose. So an important point is that when you see nothing on imaging, it doesn’t mean that somebody doesn’t have endometriosis. You can’t rule out endometriosis with imaging techniques. You can see those endometriomas, and we’re getting better at identifying deep infiltrating endometriosis with ultrasound or MRI. It’s not universally available yet, but I think we’re getting there so that we can see some of the more severe variants of endometriosis with imaging techniques. In my mind, I use it to find those endometriomas, and I use it to rule out other potential sources for pelvic pain: the tumors, the cysts, the hydrosalpinx, the infectious etiology, the adenomyosis, which we can see on imaging techniques. I rule out the other sources of pelvic pain, but you can never rule out endometriosis with any imaging technique.

Dr Hugh Taylor highlights the importance of early detection of disease and the use of imaging technology in the diagnosis of endometriosis.

Approaching the Diagnosis of Endometriosis

 Clinical Consult titled, “Updates in The Management of Endometriosis.” I’m Dr Hugh Taylor, professor and chair of the department of obstetrics, gynecology, and reproductive sciences at the Yale School of Medicine, and chief of obstetrics and gynecology at the Yale New Haven Hospital [New Haven, Connecticut]. Our discussion today will focus on endometriosis and the various factors that shape our treatment approaches to the disease. We’ll look at diagnostic tools for endometriosis, treatment options, as well as gaps in care.

It’s important that we differentiate endometriosis from other disorders that can cause pelvic pain. Endometriosis is by far the most common cause of pelvic pain in women in the reproductive age range. So it’s very likely that a woman presenting with pelvic pain has endometriosis, but we need to rule out other etiologies, that may be cysts, adenomyosis, infectious etiologies, tumors, musculoskeletal problems. There’s a whole host of other things. Our job when somebody comes in with pelvic pain is to start to think about what signs and symptoms may make it more likely to be endometriosis and rule out other potential causes of pelvic pain.

In general, endometriosis typically presents initially as dysmenorrhea. Often menarche will occur, someone will have some time with periods that are not extremely painful. These will progress to dysmenorrhea, and the pain may over time go beyond dysmenorrhea. There may be pelvic pain outside of the time of menses. There may be pelvic pain that is not specifically menstrual uterine cramps. We have to assume that some of these other pains may very well be due to endometriosis. Endometriosis typically starts with cyclic pelvic pain, typically dysmenorrhea. Endometriosis is also often a progressive disease. It may start out with dysmenorrhea that gets worse over time and then gradually go beyond the time of menses, gradually occur in other areas of the pelvis or abdomen and start to affect other organ systems. Most women with progressive cyclic pain have endometriosis. I think that’s the hallmark of the disease, that it is cyclic. If the pain is not cyclic, does not occur with menses initially, occurs randomly throughout the menstrual cycle or continuously, that’s probably not endometriosis, and start looking for other causes of the pain. If someone has extremely painful menses from the very first period at menarche, and they don’t progress or get worse, that may not be endometriosis. So I look for cyclic progressive pain, most of those women will have endometriosis.

The risk factors associated with endometriosis typically are those that would increase menstrual flow and exposure to menstrual flow. Remember, endometriosis is caused predominantly by retrograde menstruation. The menstrual flow goes backward out the fallopian tubes and into the peritoneal cavity where some of those cells implant and continue to grow. Everyone has a bit of retrograde menstruation, and we don’t know why in some circumstances that continues to persist as endometriosis, but we do know that the more retrograde menstruation someone has, the more likely they are to have endometriosis. Particularly with heavy periods, in addition to the antegrade flow, the normal period, there is probably more retrograde flow as well. Early menarche, more exposure to more periods, also is a risk factor. Things like use of birth control pills that reduce menstrual flow are protective. So not using contraceptives, not being pregnant, the more menses and the heavier the menses you have during your life, tend to be risk factors for endometriosis. One of the other huge risk factors though is family history. There is a genetic component, and probably about half the risk of endometriosis is due to that genetic component. There’s certainly an environmental component and other etiologies of endometriosis, but there is certainly a genetic component. A family history of endometriosis is a very strong risk factor.

Hugh Taylor, MD, differentiates endometriosis from other disorders causing pelvic pain and shares common risk factors for the disease.