Adenomyosis & Infertility: Symptoms, Diagnosis & Treatment

[Dr. Mark Hoffman]
Maybe later on, we can get into the, since you've discovered the origins of endometriosis, we were talking about that yesterday with my residents and it's like, the list of possible causes of endometriosis just keeps growing. Let's start with adenomyosis. What is adenomyosis?

[Dr. Keith Isaacson]
Adenomyosis is the presence of epithelial glands and stroma in the muscle of the uterus. It was a disease up until about, I'd say, six or seven years ago that was thought to affect only women in their late 30s up to menopause, that caused heavy menstrual bleeding, painful periods, and possibly painful intercourse. The reason we thought that it was only women who-- and we thought women who were multiparous, who had several children, were at higher risk for developing the disease. It turns out the only reason we thought that is because those were the women who were getting hysterectomies for their pain and heavy bleeding.

Certainly, if someone's in their 20s and having pain and heavy bleeding, they're not going to have the hysterectomy. The disease was diagnosed by histology, by taking out the uterus, and we happened to miss the disease in all the women who did not have a hysterectomy. With the advent of better MRI criteria and now ultrasound criteria to help us diagnose the disease, we realized that adenomyosis is present in women and girls as early as high school age. It turns out about 15% of girls in high school miss at least one to two days a month because of heavy or painful periods.

Now when you do ultrasound on them, you can see ultrasound evidence of adenomyosis. It's much more prevalent than we thought it was. It's now we understand that it affects all women in any reproductive age group. Certainly, probably the fact that they had had their children does probably not increase the risk of developing the disease. Everything we thought we knew about adenomyosis five years ago turns out to be wrong. We have to start over. We also know now that it impacts fertility with women with recurrent implantation failure, as well as early miscarriages and possibly even premature deliveries.

The most interesting part of this is that 80% of women who have adenometriosis present with painful periods, heavy cramping. We always thought that, okay, that's related to stage one or stage two endometriosis. You go in, you remove a low lesion on the ovary or the surface of the peritoneum, that that's going to improve. It turns out we just missed the adenomyosis in those patients. My personal bias is that adenomyosis is probably much more common and certainly presents with more common symptoms than endometriosis does. We had to have to rethink everything we thought we knew about endometriosis, as well as adenomyosis. That's where we are today.

[Dr. Amy Park]
Why would it cause infertility? Is it just produced like some bad juju? Can you explain it to me, a non-REI?

[Dr. Keith Isaacson]
Yes. I don't know about the bad juju part, but there's two parts of the myometrium of the uterus. There's the inner myometrium, which is thought to be represented in an MRI, as a junctional zone. Then there's the outer myometrium. They actually had different embryologic origins, where the inner myometrium is Müllerian in origin, and it responds to estrogen and progesterone receptors. It gets thick and thin throughout the cycle and has coordinated contractions. This inner myometrium in their proliferative phase of the cycle actually has these contractions that bring the sperm into the cavity.

In the second half of the cycle, it's either quiescent or it actually contracts to keep bacteria out of the cavity. If you disrupt that coordinated contraction, which adenomyosis does, type 2 myomas do, type 3 myomas do, that's one of the theories as to how it might impact infertility and implantation. It's just a theory. There's other theories that-- there's other juju that's been thrown out there, like the Hox10 gene, the homeopathic genes are also dysregulated in patients with adenomyosis. At the end of the day, there are a lot of theories as to why that's happening.

I think the data on looking at implantation failures in patients who have genetically screened normal embryos and even patients who have had donor embryo studies, those with adenomyosis have about a 50% lower rate of implantation and a higher miscarriage rate than those without adenomyosis. I think the fact that it impacts fertility now is no longer really controversial based on the data. The mechanism is still very, very much unknown.

[Dr. Mark Hoffman]
The other thing that is, I think, challenging for a lot of us, though, is that if we have ultrasound or MRI findings suggesting adenomyosis, then what? Obviously, infertility treatments can vary state by state. I'm in a state that is very different than Massachusetts, where you are in terms of coverage, but also with symptoms. Let's start with symptoms. I know how you treat adenomyosis is a little bit different, probably, than a lot of people treat adenomyosis, but what are the traditional treatment options for adenomyosis for symptoms, and then what are you doing differently in the same question for infertility?

[Dr. Keith Isaacson]
Let's go back a little bit just to the diagnosis, because what you'd have is, let's say you have a 25-year-old patient, which is not uncommon, who's had debilitating, painful periods, really since menarche, since she started her periods, and she's been told by her pediatrician and by her gynecologist who gets an ultrasound, that everything is normal, and they make it sound like, it's all in your head. This is normal. When you do the ultrasound yourself, and you see some of the criteria that are consistent with adenomyosis, and I tell them, I'm not proving that you have it, because I don't have a biopsy. I'm just saying you have changes that are consistent with adenomyosis.

Just the relief you see on their face like, okay, I'm not crazy, really is part of the treatment. It's just recognizing there is an explanation to their painful periods, the suffering they've had for the last 10 years, where they were told everything's normal, just suck it up. My collaborator, Linda Griffith, she had the same issue with adenomyosis endometriosis, is a professor at MIT, and they told her, they said, look, we'll give you a couch to put in the bathroom. When you have pain, you can go lay down on the couch. That was their answer. She also had breast cancer, and they gave her six months off. She says the adenomyosis was much more debilitating than the breast cancer. This is what they're dealing with.

I just want to explain that the recognition of it, just the acknowledgment that there is something that can explain their pain, is half of the treatment. The other half of the treatment is, your options are clearly, it's either medical or surgical or do nothing. Medically is the most common, where ideally one of the levonorgestrel IUDs is placed, because it's thought that the progestin that's absorbed by the myometrium is going to be suppressive, and it helps if they're not having a period. The data show that it does help 80% of the time, and the 15% to 20% that have it removed is not necessarily because the symptoms didn't go away, it's just that they didn't like the side effects.

If that doesn't work, then you have to try other types of suppression that may or may not have big side effects. You may try something like norethindrone, Aygestin, you may try a progesterone-only birth control pill, but when they take the pill, the key is to do it continuously, where they don't get a period, not where they're getting it cyclically. Then the last option is obviously surgical, and surgery, assuming they want to maintain their fertility, is very challenging. I don't do it at all for pain or heavy menstrual bleeding, but we will do it for fertility on rare occasion.

If there's a focal lesion in that junctional zone or that inner myometrium, and the patient's had a history of recurrent implantation failure, then we'll go ahead and resect that lesion hysteroscopically. The largest series of doing this is out of the Ukraine, and it was 20 patients. They had good success in 20 patients. That's a pretty small series. That Ukrainian series was done after the war, so they're still doing it. That's the largest series. Then there's a series out of Japan, where they actually do it by laparotomy, where they resect the whole back wall of the uterus and then do a flap. That works for fertility, but it also has about a 6% chance of a uterine rupture in pregnancy.

[Dr. Mark Hoffman]
Now is this like an adenomyoma we're talking about here? Because a lot of times we look at imaging or look at MRIs, and it looks a little more diffuse. There's not necessarily a specific focal lesion. A lot of us who do myomactomies will take out a myoma that turns out comes back an adenomyoma. It just didn't look and feel right, and it's a little squishy. That's a little bit easier for me to understand as opposed to more diffuse adenomyosis.

[Dr. Keith Isaacson]
Yes. I'm not sure there is such a thing as an adenomyoma. By definition, an adenomyoma is a fibroid that has a pseudocapsule that has glands in it. I don't see that very often. What I see is you're going in for a fibroid, and it's actually just crunchy tissue with no clear plane, and all that is just diffuse adenomyosis in the myometrium. It's not really a fibroid. It doesn't have a pseudocapsule. What they're doing by laparotomy typically is just debulking that. You're not removing all of it. They've had good pregnancy rate success, but again, the risk of the uterine rupture is a little high. I'm not sure.

[Dr. Mark Hoffman]
How many were in that series in Japan? Pretty small as well.

[Dr. Keith Isaacson]
Oh, heck. No. It was much larger. They've done over 1,000 patients. Yes.

[Dr. Mark Hoffman]
Talk to us about hysteroscopic surgery for adenomyosis.

[Dr. Keith Isaacson]
It has to be a focal lesion. You identify it by ultrasound, and then I try to confirm it by MRI. Then I do ultrasound guidance when I'm doing the resectoscopic procedure. You go with a bipolar loop electrode with a resectoscope, and you actually shave out the adenomyosis in that area, that focal area. It's usually about one, one and a half centimeters. Sometimes it's a cyst, which is very easy to see, which is like shelling out an endometrioma. You actually go into the cyst, and it's old blood in it, and you just have to get out the cyst wall. That part is very straightforward.

The harder ones is when it actually looks like glands, it looks like that adenomyosis that you saw by a laparotomy when you did a myomectomy, but it's just right underneath the endometrium. You want to resect that until you get to normal myometrium, and you do that with ultrasound guidance. I've been offering that to patients who have focal adenomyosis. They're select patients that have recurrent implantation failure, but I can't really tell you what the success rate's going to be yet. My series is no more than 20 as well. That's just not enough to make a-- The patients really have nothing else. It's either that, or they're told to do a gestational carrier. It's easy to tell somebody that, but it's also somewhere between $250,000 and $500,000. It's not available to a lot of people.

[Dr. Mark Hoffman]
I didn't realize it was that expensive. That's incredible. Ultrasound guidance, you're using abdominal ultrasound or transvaginal? I know you reproductive endocrinologists will sometimes use ultrasound for IVF and things like that. Normally I would use abdominal ultrasound for something like that.

[Dr. Keith Isaacson]
You have to use abdominal ultrasound for guidance during surgery. You have them fill the bladder, bring in a transabdominal ultrasound probe, and then it's helpful to see about-- particularly if you know where you're looking ahead of time, based on MRI and transvaginal ultrasound, you have a pretty good idea of where you're going to be going, but you don't want to resect any of the-- You want to resect as little endometrium as possible so that you get the best guidance you can. That's why I use all three.

[Dr. Mark Hoffman]
Are you giving them any estrogen or anything afterwards to protect aligning, to prevent Asherman's, and things like that?

[Dr. Keith Isaacson]
No. No. If they have normal estrogen levels, and this is true in patients with Asherman's as well, adding more estrogen doesn't help. The only time to give estrogen is when they're hypoestrogenic, breastfeeding, or something like that. No, there's no reason to give supplemental. The beauty is, it's like a submucous myoma. If you're only resecting one wall, you tend not to get Asherman's. The only time you get the Asherman's with myomectomies is when you're resecting two opposing myomas.

[Dr. Mark Hoffman]
I've heard some opponents of global endometrial ablation for that reason, that if you do hemiablation and just use the old rollerball and do half, your chance of getting an Asherman's is so much lower because you don't have two burned sides opposing the other, and it sounds like it's the same theory.

[Dr. Keith Isaacson]
Right. That's exactly right. Plus, you don't want to resect too much endometrium. You want to keep it focal, or the interest of the patient. Because the other alternative for treating this in patients trying to get pregnant is two to three months of a GnRH agonist prior to a frozen transfer. The data's pretty good that your embryo implantation rate is about 50% of what you would expect if they have adenomyosis in the endometrium. If you pretreat with a GnRH agonist for two to three months, and then you go through the frozen embryo transfer protocol, you'll get your implantation rate back to normal. Let's say it's normally 30%, 15% without treatment, you treat them, and it's back to 30%.

Again, the ones that I do surgery are the ones who say, oh, bad as well. I always try the medical treatment first. The only time I do the surgery is when their next step is they were told to have a gestational carrier. I feel like we have nothing to lose, because I don't think it's a risky surgery. I do think it just helps that you-- if you're fast-sawed with a resectoscope, because the tissue shavers won't work for this. If you're pretty good with a resectoscope, it's pretty straightforward.