Endometriosis Foundation of America
Endometriosis 2013 / The Role of Medical Therapy after Surgery
Jon Einarsson, MD
I would like to thank Tamer and the organization for inviting me to give this talk. I only have 15 minutes so I am going to try to make it count.
We all know these figures about endometriosis; I am not going to go into that. It is interesting though that endometriosis actually sometimes will resolve spontaneously, sometimes it progresses and sometimes it is stable. It is not always a progressive disease. It is important to keep that in mind. It is also important to keep that in mind that surgery is effective but endometriosis can certainly come back. You take out this big nodule there, you feel really good about yourself but it does not mean that the endometriosis is cured. It certainly can come back. It is a dynamic disease and there are several studies do show that. Some of them are listed there. At the bottom this study by Patrick Young on teenagers showed that there was a 47 percent reoperation rate in that group. But none of those patients had endometriosis when they were re-operated so it highlights the fact that these patients have pain but the pain may not be coming from endometriosis. Pain is certainly multifactorial in these patients. So to think that you are going to cure all these patients by excising the endometriosis that is just not going to happen.
It is interesting that there was a big discussion about hysterectomy just now and I am just going to put some data onto that discussion. Because the type of surgery definitely affects the recurrence risk and if you look at this study that was done by Falcone et al at the Cleveland Clinic it was interesting that the patients that had conservative surgery, i.e. patients that kept their uterus and their ovaries, they had a much higher recurrence rate. The patients that had a hysterectomy almost had the same recurrence rate as the patients that had a hysterectomy and an oophorectomy. If you break it down by age that is also interesting because if you look at the age group of 19 to 29 at seven years 72 percent of them had a recurrence as opposed to if you have the age group of 40 there is a much lower recurrence risk. Also interesting is that in the age group of 30 to 39 whether you removed the ovaries or not at the time of hysterectomy the recurrence rate is actually very similar. Removing the ovaries in a 30 something may not be beneficial but removing the uterus is very beneficial. You can see the recurrence risk is 56 percent if they only had laparoscopy but only ten percent if the uterus was removed.
In my practice if the patients are done with fertility I will definitely advise removing the uterus. Obviously I will tell the patients that they may not be cured but it increases their chance of becoming cured significantly and I do not think that is a great part of the procedure honestly. It takes me maybe ten or 15 minutes to do the hysterectomy but it may take me two hours just to get there. Just to get down to getting the hysterectomy done, so to me that is just a minor part of the procedure and should be done if the patient consents to it and if they have completed their child bearing obviously.
My task today was to talk about medical therapy following surgery for endometriosis. The point of the earlier slides was that endometriosis certainly comes back so what can we do to prevent that? There are several options and some of them are listed here and I am going to go through them very briefly because, again, I do not have a lot of time but I am going to try to review some of the literature on some of these options.
Birth control pills certainly are probably the most affordable long term therapy until pregnancy. Not all patients are good candidates as we all know. One randomized trial in 311 women who underwent laparoscopic excision for symptomatic endometrioma was divided into three groups. They had no therapy they had cyclic and continuous OCPs for two years. There was actually a significant reduction of the recurrence rates and VAS scores for dysmenorrhea in the continuous users versus the cyclic and the non-users. But there was no difference in recurrence rate and VAS scores, however, there was significantly more increase in dysmenorrhea, dyspareunia and chronic pelvic pain at 6 to 24 months among non-users. It does seem to be beneficial to use birth control pills, particularly continuous birth control pills.
There are alternative delivery methods for combined estrogen/progesterone treatments. This is a co-ed study done by Vercellini and associates where they took 207 patients and they had recurrence of endometriosis related pain. They gave them either the vaginal ring or the transdermal system for 12 months. The women using the vaginal ring were significantly more satisfied and showed better compliance with treatment. Both systems reduced pain but the vaginal ring was a little bit more effective in treating dysmenorrhea and rectovaginal lesions. But there was a significant amount of withdrawals because of side effects and much more in the patch users.
Progestins are another option. There are several potential mechanisms of action for progestins in this disease and some of them are listed there. You are also avoiding some of the estrogen associated risks. But progestins do have side effects and are often not well tolerated by the patients. Some of the more common progestins are listed there; there is Provera, Medroxyprogesterone acetate, there is Aygestin (Norethindrone acetate), there is the Depot Provera and the Mirena IUD. Those are probably the most common ones.
There are studies showing that all of these things work in patients that have endometriosis. But there are side effects like I mentioned and some of them are listed here. As a result a lot of women are not often able to tolerate this treatment long term.
The Mirena IUD has not been shown. There are three, small randomized trials showing that this is actually effective in reducing the risk of reoperation in patients that have conservative surgery for endometriosis. The first study was done by Vercellini is often cited but there two other small studies that have shown similar results. It certainly is a good option in these patients. Compliance is fairly high and obviously we all know the distress to the patients when they may have irregular bleeding for several months. Try to encourage them to keep the IUD in because it may not take effect until much later. Interestingly, one study did second look laparoscopy and they actually found reduction in endometriosis lesions after the Mirena was inserted. Potentially the Mirena sort of effecting a local effect not just on the uterus but in the pelvis as well.
I know that there are a lot of surgeons here and I certainly am included and I like to operate on patients with endometriosis. But sometimes we may want to ask ourselves, you know, should we be operating on these patients? There is a lot of evidence, or some evidence, suggesting that potentially medical treatment may be effective as well. I know that is sort of a heresy to mention that potentially here. At 12 months a medical therapy group was actually doing a little bit better in two aspects including frequency of intercourse and overall satisfaction with their treatment. There was no difference in these validated health questionnaires. Essentially these two treatment options were equivalent.
Surgery is hard to define because we all know surgery is not surgery the quality of surgery can be very different and a lot of people think because they do their surgery so well they never have recurrences. But I think we all had recurrences. I think we have to face that reality and certainly experience is important in this but I think we all have recurrences no matter how aggressive we are.
Progesterone antagonists have also been evaluated. There is less data on that but Mifepristone has been evaluated for this as well as asoprisnil. There is not a lot of data though on post-surgical management. But I do want to mention these are potential options and they have been shown in preliminary studies to be affective.
Danazol is obviously something that has been around for a very long time and it works on endometriosis by several different pathways, some of which are listed there. There was one randomized study comparing 600 mg of Danazol versus placebo in 77 women with moderate or severe endometriosis. They gave this to the patients for three months after surgery and there was actually no difference in pain relief six months after finishing treatment. Maybe that does not really work that well. Plus it has a lot of side effects, unwanted side effects. It is low on my list at least as a treatment option.
The GnRH agonists we all know are often used after surgery. There are seven randomized trials on the use of GnRH agonists after surgery in an effort to reduce re-operation rates. There is actually very mixed results. Five trials had no positive effect or no effect. Two trials had significantly low risk of recurrence after surgery with the use of GnRH agonist. Now is that because in the five trials where there was no effect the surgery was so good? It is hard to know. There is obviously some bone loss but if you use this for six months it should be reversible and you can use add back therapy in order to reduce that risk. Norethindrone acetate is something that we use routinely but you can also use a combination of low dose estrogen/progesterone.
There is one study here that was looking at GnRH agonist versus progestin so it was a randomized study using Dienogest daily versus Triptorelin, which is another GnRH agonist. There were a lot of protocol violations but among the patients that were studied there was actually no difference in efficacy between the two groups. They were similarly affected. This medication is available in the United States so you can use it but it is only available as a combination birth control pill. It does contain 0 to 3 mg of Dienogest.
So GnRH antagonists are another way of treating endometriosis. No studies that I am aware of where they are used in post-surgical management but in the sort of compared management of endometriosis related pain there are some very preliminary data showing that it does seem to be affective. But we just do not have enough information I think to make any significant conclusions.
Aromatase inhibitors are a very promising group of medications that are being used. Endometriotic lesions they contain aromatase and they can make their own estrogen potentially. Letrozole and anastrozole are the ones that have been most commonly used. They are usually used in combination with some other type of ovarian suppressive medication like birth control pills, progestin or GnRH agonists. They are usually used for refractory pain for rectovaginal endometriosis. There was one randomized trial that found that there was less pain with letrozole plus Norethindrone versus just using Norethindrone. Another randomized trial compared six months of GnRH agonist therapy with anastrozole versus GnRH agonist therapy alone. There was actually significantly longer time for symptom recurrence in the combination regimen. Maybe aromatase inhibitors are something that we should at least be considering.
Here is another randomized trial comparing 106 women to letrozole or aromatase inhibitor versus Danazol and pain was actually significantly lower in the letrozole and Danazol groups versus placebo. So they were actually found to be equally effective in this study. So this is a little bit - the data is a little bit heterogenous. Another randomized trial of 144 women after endometriosis compared letrozole versus GnRH agonist and placebo. They only used it for two months so it is kind of a short treatment regimen. The rate of recurrence was similar in all groups at one year.
There are selective estrogen receptor modulators as well and there is only one double blind prospective study in 93 women after surgery using raloxifine versus placebo and they actually found that - they did interim analysis and they stopped the study because it did not seem that the selective estrogen receptor modulators were effective.
In summary, in my practice what I do is first line therapy in these patients. I do think that endometriosis will come back and I am sure that I leave endometriosis behind a lot of times and so I do recommend that these patients have some sort of post-surgical medical management. Obviously compliance is important so you want to pick something that they are going to potentially keep using, hopefully. I tend to prescribe continuous birth control pills or Norethindrone acetate or the Mirena IUD. I give them those three options and I tell them a little about the pros and cons and let them decide what they want.
Then second line, and this is just my sort of mind there are not any national established guidelines - second line you can use GnRH agonists with add back. At my institution Dr. Hornstein and others have used GnRH agonists for a very long time, up to 15 years with add back and those patients actually do very well. They monitor their bone density. I have had to operate on some of these patients though because I had one that had been using that for maybe 11/12 years doing well and then suddenly she just had pain come back. We operated on her and she had a lot of scarring and endometriosis.
I am almost done. Third line therapy - aromatase inhibitors are I think very promising but I think we need just a little bit more data and they are also fairly expensive but certainly something to consider. I think Danazol is low on the list because of side effects. And then progesterone antagonist - probably also we need more data on that.
I want to close with this study here. I could not resist putting this study up here. This is an actual study published in Fertility and Sterility earlier this year. I just came across it and I just wanted to make sure I did not miss anything and I was not aware of this study. Nobody but the Italians would have done this study. If I had put this through my IRP they would have been like "what the hell are you doing?" They looked at 300 nulliparous women and they had four independent observers evaluate attractiveness on a scale from five, very attractive to one, not attractive at all. They actually found that the women with rectovaginal endometriosis were significantly more attractive than the women that did not have endometriosis or the women that had superficial endometriosis. They also found that those women had intercourse earlier, they had a leaner build and larger breasts - I am not making this up - there was no difference in eye or hair color between the groups. Their hypothesis is that women with higher estrogen levels had been found to have more feminine, attractive and healthy looking faces than those with low levels. And high estrogen levels may be associated with endometriosis and these other bodily features that were mentioned there. That was their hypothesis but I just wanted to end on that interesting note.
Thank you very much for your attention.