SESSION II: Treatment considerations
Keith Isaacson, MD
Adenomyosis and infertility
Scientific Symposium
Advancing the Science and Surgery of Endometriosis
Monday and Tuesday, April 18-19, 2016
The Union Club, New York
Thanks for the invitation and to Harry for organizing this and arranging it and for Tamer for putting it on every year. It is an honor to be here. I will go quickly but I want to discuss adenomyosis because I really think we have to re-think the relationship between the symptoms we have always attributed to endometriosis and the presence of adenomyosis.
Just for a little background, I will go briefly. Adenomyosis by definition is endometriosis glands and stoma present in the uterine musculature with adjacent smooth muscle hyperplasia and fibrosis. It can be focal or diffuse and when patients have a hysterectomy, which is how the disease has been diagnosed for many years it is found anywhere from 20 to 48 percent of the time.
It was first described in 1860 but the current terminology was described in 1972. It is relatively a modern diagnosis. One of the problems with adenomyosis is that we do not have standardization of the definition even a histological definition. These are three of the most common definitions of adenomyosis: the first of which is endometrial glands within the myometrium greater than one low power field from the basalis layer of the endometrium. The second is endometrial foci being deeper than 25 percent of the myometrial thickness and the third is glandular extension anywhere from 1 mm to 3 mm below the endometrial layer or 2.5 mm below the basalis layer. All three of those definitions are currently being used. Typically if you go to your pathology department you will find that each pathologist within the department has their own definition of adenomyosis, at least at the Harvard Hospital there is not one standard histological diagnostic criteria, which is a problem.
So the clinical presentation of adenomyosis by far the most common presentation is heavy uterine bleeding. Thirty percent of these patients present with dysmenorrhea. Some present with back pain, dyspareunia that we heard a little bit about in the previous lecture. I am going to focus on infertility.
The question is how do we make the diagnosis of adenomyosis? Well, the most helpful I think is a history. When you take the patient’s history you have a pretty good idea that she is going to likely be suffering from adenomyosis just by talking to her and discussing her symptoms. But the classic way prior to hysterectomy has been with the use of an MRI and as we all know the value of the MRI, the cost of the MRI is very expensive therefore it is underutilized, which it should be and so patients were being underdiagnosed.
Now we are going to talk about the data that we are getting from ultrasound. Most gynecologic practices do have ultrasound in the office and are able to diagnose this disease very accurately, a lot more commonly and a lot less expensively. We can also use hysteroscopy but again as we talked about the diagnosis is typically confirmed by histology, which has been a hysterectomy specimen.
What we are looking for with an MRI is a large asymmetric uterus, a thickening of the junctional zone, an increased ratio of the junctional zone to myometrial thickness and then we look for foci low signal intensity within the myometrium. This is an interesting picture. When I got this it described the adenomyosis from this particular article. What is interesting was that they were measuring here the junctional zone and saying how thick it was and this was how they made the diagnosis of adenomyosis. What they missed, which is obvious probably to everyone in the room here is look at this deep infiltrating endometriosis that is going from the adenomyosis to outside the uterus into that rectovaginal space. They did not even talk about it in this article. All they were talking about was this was from a radiological journal looking at the thickness, missing the deep focal adenomyosis as well as the deep infiltrating endometriosis.
The reason I say now we have a problem is now we can make this diagnosis with ultrasound just as accurately as you can with the MRI. So we are making the diagnosis of adenomyosis in these adolescent patients which we discussed this morning. I just recently found adenomyosis in a 17-year-old by ultrasound and now we have to figure out do we have to rethink all these symptoms that we had attributed to endometriosis are very, very likely due to adenomyosis. What the heck are we going to do about it because you cannot go in there and resect adenomyosis like you can endometriosis. This is why I say we are going to be able to make this diagnosis but we also have a problem as to how we are going to manage it.
With the ultrasound studies, I will just show you an example here, this is by ultrasound this is an MRI. By ultrasound it is very obvious you can see here is the endometrial echo. You see asymmetry of the thickness of the myometrium just as you do with MRI.
The ultrasound criteria, and I give a lot of credit to Caterina Exacoustos from Italy because she has done the pioneering work with the ultrasound criteria. She is looking at a junctional zone variation which she calls the junctional zone difference of greater than 4 mm, which is the thickest portion of the junctional zone minus the thinnest portion of being greater than 4 mm. The maximum junctional zone thickness of 12 mm, myometrial asymmetry, myometrial cysts, striations, Hocky stick of the endometrium and reduced Doppler flow within the myometrium where there is focal adenomyosis. The key here is that when you send a patient to the radiologist and they say there is no fibroid there they will say the exam was normal, the uterus was normal. But if you know the patient’s symptoms and you are doing the ultrasound yourself you know to look for these areas and you are going to find adenomyosis in the patients that have dysmenorrhea, even the young adolescent patients that have dysmenorrhea, dyspareunia and back pain. It makes so much sense when you think about it. When you have a patient that has stage one endometriosis and she has got a peritoneal lesion that Dr. Seckin showed you this morning, how does that cause cramping, severe cramping during menses? It probably does not. Probably that patient has adenomyosis but we did not know to look for it. I promise you, if you are aware of it and you learn how to do the ultrasound yourself and you have the patient’s history you are going to find it.
This is an excellent study by Danielle Luciano and Caterina Exacoustos. They looked at 54 women prior to hysterectomy, looked at at least two ultrasound features that we mentioned for adenomyosis. The diagnostic accuracy if the patients were not treated with any type of hormonal suppression was 90 percent. If they were on hormonal suppression it was harder to diagnose it was only 50 percent. But look at this you had a positive predictive value of 99 percent with the ultrasound. This is with a biopsy proven diagnosis based upon the ultrasound findings.
Just some examples of things; some of these are from my patients and some are from the literature. If you look – here is the endometrial echo – we often find these little cysts within the myometrium in the patients with dysmenorrhea. If you are doing the three dimensional scan yourself you could see the cyst just below the basalis. Here is another one here, this again this is focal adenomyosis if you are doing the transvaginal ultrasound yourself and you know that if you see the uterus going off to the right hand side she is retroverted and if it is going to the left hand side she is anteverted. You most often find adenomyosis in the posterior wall so this is a retroverted uterus. You see this hyperechoic space with this cyst. This is focal adenomyosis. This is a patient and here again you can see the cyst right here. This patient had gone to the radiologist they said they did not see any fibroids she had hypermenorrhea at the time so they said it was normal. This is not normal. This is a patient who has adenomyosis.
In a paper that is currently in press that the authors Beryl Benacerraf and her group she is suggesting that a patient come in and get a thorough ultrasound for infertility evaluation and part of which, what she is looking for if you see on this 3D exam as well as on this 2D you will see these cysts within the myometrium. This is a patient with infertility that has classic adenomyosis by ultrasound criteria. It is just as good and maybe even better than the MRI.
Hysteroscopy is part of our infertility evaluation in our practice offices hysteroscopy is. There are some findings that you will see, pitting of the endometrium toward the myometrium, which again is pathognomonic for adenomyosis. This is a still picture where you can see this pitting of endometrium toward the myometrium in patients that have had adenomyosis.
Adenomyosis – what is its relation to fertility? That is a great question because all our patients in the past had treatments in which they could not get pregnant. They were either placed on a Mirena IUD or they were given an endometrial ablation or they had a hysterectomy. Was there a relationship, is there a relationship between adenomyosis and fertility? If you go back and look at the baboon data from 2004 they looked at 37 baboons with adenomyosis and 38 without adenomyosis based on necropsy. The odds ratio that these baboons had endometriosis was 31.5. Lifelong infertility with adenomyosis the odds ratio was 20.6. If they only had endometriosis without adenomyosis the odds ratio of infertility was only 3.6. At least in a baboon model the adenomyosis was much more important for creating infertility than the endometriosis by itself. Take patients who have deep infiltrating endometriosis with and without adenomyosis. If they looked at their pregnancy rates, this is from Vercellini 2014, if they had deep infiltrating endometriosis with adenomyosis only seven out of 59 of these patients conceived. If they had deep infiltrating endometriosis without adenomyosis 74 out of 172 conceived with a reduction in pregnancy rate due to adenomyosis itself of 68 percent. So the adenomyosis was at least, if not a more, important impact negatively on infertility than the endometriosis itself.
There are lots of studies. This is out of Japan. They looked at 413 patients undergoing in vitro fertilization and just looked at those who had asymmetrical myometrium. If the myometrium was thicker on one wall than the other wall then these patients had suggestions of adenomyosis, they had lower implantation rates, lower clinical pregnancy rates and lower live birth rates.
I am the first to admit that the data out there are not always consistent. This was an article of a group that looked at adenomyosis in patients undergoing in vitro fertilization but these patients had no symptoms. They had no dysmenorrhea, they had no dyspareunia they just happened to find it on ultrasound and their conclusion was that the adenomyosis in this patient did not affect the implantation rate in patients with asymptomatic adenomyosis.
There are lots of studies, I am just going to breeze through them because they are all – and I will go through this one which I think is probably the best. It was the most comprehensive published in Human Reproduction 2014 by Vercellini’s group and again looked at the impact of adenomyosis on in vitro fertilization outcomes and what they found was that they had a lower implantation rate. The clinical pregnancy rate was about the same in this group between the controls. They had a higher miscarriage rate and they had a statistically significant lower live birth rate. It does seem that at least with in vitro fertilization adenomyosis adversely impacts the outcome.
How are we going to treat this now that we find it? The suppressive therapies and the surgical treatments all prevent fertility. In your young adolescent patients you are obviously not going to use anything that is going to compromise their long term fertility.
Fertility enhancing therapies include GnRH alone, ART, surgical resection and ablative therapies. GnRH alone very, very small amount of data on these cases as far as the impact on fertility. However if you do use it and you use it for up to one year it did seem to help the fertility for six to 12 months but after 12 months the infertility rate was back to baseline.
Now surgical excision is what I really want to talk about and I am sorry I am running a little late on this. Let me go through the surgical excision and what we do here. With surgical excision this was described in Japan you go in and you just try to find the plane between the adenomyosis and what appears to be normal myometrium. You resect that out and those of you who have been in this position where you thought you were going to get a fibroid and you find adenomyosis you know how difficult this can be. You resect that as much as the adenomyotic tissue as you can and then you just repair it. This was one of our cases that we were doing. I will fast forward it. We have cut into it. This is all adenomyosis in the posterior wall. We are using just a bipolar spatulate to cut it out. I will see if I can advance it for you, and it is just piecemealing it out because you can see normal myometrium here. All this is adenomyosis and we just cut it out a piece at a time until we get to what we think is normal myometrium. Then just sew it up like you would a myomectomy in multiple layers, usually it is a three or four layer closure. It does not bleed a lot which makes sense because the fibrotic tissue is not hypervascular. It is just a difficult, tedious surgery because you are trying to get out all that tissue that does not have a good pseudocapsule around it.
If you look at who will benefit from this uterus sparing surgery in subfertility this is a study by Kishi who looked at a 102 women who underwent that type of surgery on their uterus. Again, in patients who were under 39 years old they had a 41.3 percent pregnancy rate. If they were over 40 years old they only had a 3.7 percent pregnancy rate. For them it was most important that the patients were younger when they had this surgery. What they also found was that it was a worse prognosis if the adenomyosis was in the posterior wall and a worse prognosis if they had co-existing endometriosis.
Grimbizis looked at the operative treatment for adenomyosis, nine studies of 469 patients. He looked at whether or not they had complete excision or incomplete excision and the pregnancy rates were very similar, which were actually fairly high, 60 percent pregnancy rate with complete excision and 47 percent with incomplete excision.
Other ways to treat adenomyosis if you do not feel that you have the technical expertise to do that resection you can try to burn it with monopolar or bipolar energy. Typically it is not recommended for patients who want future fertility. MR guided focused ultrasound has been used but all we have are case reports as to whether or not it works.
The bottom line in summary is that I do think that adenomyosis clearly affects fertility. You have heard from Dr. Fazleabas this morning that we see a decrease in expression of progesterone receptors. We see dysregulation of various genes. We know we have endometrial inflammation and we have various alterations in some key cytokines.
I throw out infertility there because the topic was not on the list to discuss today and I think it is important. I think our biggest question for all of us in the future is what is really the impact of adenomyosis now that we can diagnose it by ultrasound versus the impact endometriosis that we can easily see by laparoscopy and we can resect? We do not have that answer and I have got a feeling that it is much, much larger than we currently appreciate. I think some research questions we need to characterize the adenomyosis environment. We need to understand what are the cytokines present, what are the cells responsible for producing these cytokines? We need to understand the importance of smooth muscle and we certainly need to increase the awareness and understand the true prevalence of the disease. With that I will stop. Thank you very much.
