Endometriosis Foundation of America
Medical Conference – 2012
Can Early Detection and Treatment of Adolescent Endometriosis Prevent Adult Endometriosis?
Thomas D’Hooghe, MD, PhD
Thank you very much Mr. Chairman. I would like to thank Dr. Seckin for the very kind invitation and his hospitality during this meeting, this very interesting meeting with the focus on endometriosis in adolescents.
My topic will be the clinical question whether early detection and treatment of adolescent endometriosis can actually prevent adult endometriosis. I give this talk on behalf of two of my colleagues, one being Dr. Christel Meuleman, who just got a PhD, partly on studies on adolescent endometriosis, and she is the lead surgeon of our endometriosis research group, and Professor Hoppenbrouwers who is actually a professor in adolescent and child health at our university. We try to work together in this field of adolescent endometriosis. I work in Leuven University Hospital, which is located in Belgium, a small country in the west of Europe. Our hospital is actually one of the largest teaching hospitals located closely to Brussels and one of the oldest universities in Europe, founded in 1425.
I want to go through four issues with you. What is the prevalence of endometriosis, what is the prevalence of pain complaints in adolescents, how can we detect early endometriosis, what are the tools, or which tools do we need to develop, and finally the question, can early treatment indeed prevent adult endometriosis?
We all know endometriosis, no need to repeat this information. It is a chronic inflammatory reaction related to ectopic endometrium mostly located in the pelvis. We can look at it as a disease which can be staged in various forms of severity. ASRM classification being the most used classification and in terms of phenotypes we can distinguish three although they do not necessarily present different disease. They often co-exist but I think that there is consensus that you can look at it from the peritoneal disease point of view, ovarian endometrioma and the deep infiltrative endometriosis point of view.
So let us start with the first question, what is the prevalence of endometriosis in adolescents? First we need to know that all of the evidence here is obviously highly biased because you only would know in adolescents who present for a clinical problem which requires laparoscopy. Taking into account that limitation nevertheless it is possible to do a systematic literature search which we did for the last 30 years. Key words: endometriosis, laparoscopy and adolescents and chronic pelvic pain. This has now been submitted to Human Reproduction Data and invited review. We started with 1,014 studies then 89 were left and read thoroughly and only 15 were studies that were selected because these were really studies looking at prevalence, not at just like documenting endometriosis in adolescents, but really as main, primary outcome the prevalence of endometriosis. The total number of patients covered was 893 and here are the results. The overall prevalence of endometriosis in adolescence with chronic pelvic pain, and/or dysmenorrhea resistance to OCPs and NSAIDs is 62 percent. If you look at the subpopulation of girls with chronic pelvic pain resistant to OCPs it is as high as 75 percent. That is more or less similar as the ones with dysmenorrheal, and the ones who have chronic pelvic pain just mentioned as a general problem, have 49 percent prevalence. Surprisingly, the proportion of girls with moderate/severe endometriosis is one in three, 32 percent, which goes against our belief system. But these are the data so this important. We need to be prepared even in adolescents to treat moderate to severe disease. Also here, the prevalence is higher this time in the group with chronic pelvic pain than in groups with chronic pelvic pain resistant to OCPs or dysmenorrhea, which is again a bit strange, but these are the data.
If we then look at how moderate and severe endometriosis is described in these girls, actually this was done in only three of the 15 studies, and it reads much like adult endometriosis; rectal lesions, tubo-ovarian adhesions, extensive disease on the peritoneum ovaries, tubes and surrounding structures, rectovaginal, uterovesical, bowel and ureteric and endometriosis. So it is all the same happening at least in the proportion of adolescents. That is why we need to reconsider how we look at adolescent endometriosis. It is not only about superficial lesions, peritoneal lesions it can also be about ovarian endometriosis, ovarian cysts and even deep endometriosis, which we have seen by the previous speaker needs to be treated adequately and which we also treat with the laser surgery in our center. This part of endometriosis is particularly challenging as we all know. We completed a systematic review published earlier last year on the surgical treatment of deeply infiltrating endometriosis with colorectal involvement. Forty-nine studies were reviewed, close to 4,000 patients, and whereas complications are reported fairly well in 94 percent of the studies and pain is reported in two-thirds, but look at the under-reporting regarding quality of life. Only ten percent of studies also used various measuring and reporting modalities for symptomatic efficacy, recurrence 40 percent, fertility less than 40 percent. The main problem in this field of our research where we need to do much better in terms of prospective outcomes that is with well-defined terms and definition to do these studies.
In our center we use this laser approach but more importantly we use a multi-disciplinary surgical approach with Dr. Meuleman as the lead surgeon in our group. And for specifically the surgery with deeply infiltrative endometriosis with colorectal extension we believe it is fairly important to preserve as much as possible fertility in the future. We published two retrospective case series and are now submitting a prospective controlled study in women with moderate/severe endometriosis. Overall the results, I would just focus on I think the most relevant thing, fertility, about 50 percent will become pregnant afterwards, and importantly, of those who become pregnant 40 to 60 percent actually achieve spontaneous pregnancy, so no need to go to IVF. In this study, which is not yet published, we were able to show that in the group with moderate to severe endometriosis if you have one group which receives a bowel resection for deeply infiltrative endometriosis, and the other one does not receive bowel resection because they do not have bowel endometriosis or the bowel endometriosis does not require resection, actually for fertility it does not make a difference. Fifty-one percent will become pregnant, and 41 percent will become pregnant spontaneously of the 51 percent who achieve a pregnancy. Of the ones who received a bowel resection 58 percent became pregnant spontaneously whereas the ones without bowel resection 42 percent. This just shows that a bowel resection with the right indication does not necessarily impair natural fertility. This is important of course for adults with endometriosis. But it is also relevant for teenagers with endometriosis although obviously we do not see in teenage endometriosis this deep infiltrative endometriosis with colorectal extension so frequently, luckily. But it can happen as I showed in the previous slide.
We know the prevalence is high in selected populations. The next question is what is the prevalence of the preceding problem, the pain? What is the prevalence of menstrual cycle related pain problems in adolescents? Again, we did several studies which have not yet been published. We looked at a very young group, 12-year-old girls in Flanders and this is the first large population based study on characteristics of menstrual cycle and related complaints in young teenage girls at or shortly after menarche. Close to 800 girls actually completed the questionnaire out of more than 5,000 that were part of this larger cohort study. We had developed a semi-structured questionnaire and the results out of 363 girls who actually had reached menarche at the age of 12, 42 percent reported painful menstruation. The likelihood of this painful menstruation decreased approximately 50 percent for every year that age of menarche increased. Later menarche seems to be protective against the development of dysmenorrhea and most likely also endometriosis. Painful menstruation was positively correlated with the duration of menstrual flow and the amount of blood loss. There was a negative impact on social activities generally speaking in one in four girls, but if you select this group it actually reports painful menstruation, 41 percent had actually a negative effect of menstruation on social activities, more so than girls without painful menstruation.
Then, if you look at another group – we have moved from 12-year-old girls to 13 to 16 year-old-girls and then from 17 to 21-year-old girls. This is a study done in the high schools in the Leuven University neighborhood. This is a study done in first year university female students. If you look here, the prevalence of menstrual pelvic pain reported often mostly are always 41 percent, 52 percent and then plus also a visual analogue score of seven or more, which can be considered to be severe pain, 16 to 17 percent overall comparable. Non-menstrual pelvic pain occurs less frequently. Impaired quality of life during menstruation: 11 to 12 percent. Current use of hormonal contraception: ten percent in the 13 to 16 year olds, 66 percent in 17 to 21 years old, logically speaking. The indication to use hormonal contraception as an analgesic: 40 percent in both groups. Forty percent just uses these pills, not for prevention of conception, but as an analgesic.
Then the proportion of girls and young women with chronic pelvic pain refractory to OCPs or NSAIDs: four to five percent and the combination of both: one to three percent. I think this is the population we need to look at. One in 20 or about one girl in every class, let us put it that way, has a type of pain which is very likely to also be affected by endometriosis. This is the group of girls we want to see in our clinics for early diagnosis and early treatment. This group not only presents with typical gynecological problems but also with lower back pain, at least one urological symptom, at least one GI symptom. If you look at the group of adolescents here and the group of young women overall you can say that the menstrual pain is much more pronounced than the non-menstrual pain. That is true for both groups for lower back pain, urological symptoms and GI symptoms. If you look at the trend, of course this is not direct, but if you look at the trends comparing how these symptoms actually evolve from adolescence to young adulthood it seems like there is an increase in lower back pain proportion during menstruation: 26 percent, 38 percent. Lower back pain reported not only as frequent but also as severe: eight percent to 13 percent and urological symptoms remain in more or less the same and GI symptoms also seem to increase a little bit. Of course, this is indirect evidence but it seems to imply certain trends.
Now, let us move to the next question. How can we detect these pain problems at an early stage? And how can we improve timely referral to centers of expertise? We know quite a bit about this. We know if you look at all the evidence which is available, specifically for adolescence, we know that there is a reduced risk of endometriosis if menarche is older than at 14 years. We also know the increased risk for endometriosis compared to girls without endometriosis if there is frequent occurrence of early dysmenorrhea. If we look at the specific risk profile for deeply infiltrative endometriosis we know that those girls with a positive family history of endometriosis, with increased frequency and duration of oral contraceptive use for severe prominent dysmenorrhea, and those with increased frequency of school absenteeism during menstruation, those are all risk factors for endometriosis.
We need to use this information to develop a questionnaire which can be used in primary health care. This is what we have been working on over the last few years. We first did a systematic review to identify those questionnaires that measure quality of life with girls with endo and chronic pelvic pain and we selected the three best ones with the highest relevance which is the EHP 30, the questionnaire developed by Dr. Kelechi Nnoaham a study by the World Endometriosis Research Foundation published in 2009, and then the questionnaire developed by Melissa Parker in Australia, published in 2010. We believe those three are the best existing ones. We then compared these questionnaires to three other existing questionnaires developed within our own university as part of past research. We compared them, the three international to national ones, and developed a new questionnaire based on the best elements of these questionnaires plus the scientific evidence about risk factors. This is now being done but it is not final yet of course because once you have a questionnaire you need to validate it. Just a questionnaire in itself is not necessarily added value unless you validate it and it has scientific value. This is the next thing we want to do. And then test it and integrate it into routine developmental surveillance practices of health care workers who take care of adolescent girls, and see whether we really reach the target to have those girls with significant problems and actually diagnose and treat them for their endometriosis.
We believe strongly, and we published this paper a number of years ago together with Lone Hummelshøj on centers of expertise, at the time labeled centers of excellence but expertise is a better word, that the concept should be that there is the woman (or the girl) and the gynecologist and they are the decision making team. This applies to adult endometriosis but even more so to adolescent endometriosis because the girls still have everything ahead of them, fertility, relationships and sexual activity – it all has to happen. There is an enormous responsibility here to guide the girl (the woman) through the whole process of reproductive life with endometriosis, and work together with a number of specialists as they are needed with surgery, in my view definitely as the primary method to diagnose and treat endometriosis.
Then finally, if we then see endometriosis and we treat it can we prevent adult endometriosis? The answer is simple, we do not know. Why do we not know? We have not done the research. There are only three retrospective and one prospective case series published so far to the best of my knowledge. If you look at the overall picture here the effect of surgery shows some improvement but there is often recurrence or persistence of pain in this specific group. About 50 percent require repeat surgery. If you look at the effect of post-operative hormonal suppression, if we do not give it progression has been reported; if we give it, same problem - persistent recurrence of pain, significant side-effects leading to compliance problems. This is the overview. I briefly will go through these four studies together with you.
The first one is, if you do surgery and you do not give post-operative hormonal treatment what happens? This is an interesting although very small study, a retrospective case series of three patients between 13 and 16 years old. The presenting symptom was pelvic pain resistant to continuous oral contraceptives and pain killers. They all received diagnostic operative laparoscopy. Minimal endometriosis was found and they did not want to take the hormonal suppression therapy. Why? Because of side-effects; depression, irregular bleeding and fatigue, so they simply stopped it. Then they came back because the pain came back. Repeat laparoscopy for recurrence and worsening of pelvic pain showed progression to severe or mild endometriosis. There was progression in all three of the patients with actually one of them developing deeply infiltrative endometriosis, one an endometrioma and one diaphragmatic endometriosis. A very small series but it suggests at least that if you do not give treatment in a selected group of girls, endometriosis may progress at a young age, which explains why moderate/severe endometriosis indeed can be found in adolescents.
The second study: retrospective case series in an interesting, fairly large group, a highly selective group of 90 women with a median age of 17 (not seven). They were 17 years old at the initial laparoscopy. The inclusion criterion is interesting. It is pain exacerbation after laparoscopy one during hormonal suppression, so they had had an operative laparoscopy, they were receiving hormonal suppression and under this hormone suppression they had pain exacerbation. The first laparoscopy was actually done already for pelvic pain resistant to hormonal suppression and NSAIDs. Average minimal endometriosis was found although there were some cases with moderate endometriosis as well, not really specifically mentioned in the paper how many. Then they received, after the first laparoscopy postoperative hormonal suppression in all patients, 91 percent continuous oral contraception, 78 percent GnRH plus addback, 12 percent progesterone only pills and as you can see many received a mixture of these types of treatments. Those who still had pain during this hormonal suppression got a second laparoscopy. This was 90 patients inclusive. The median time: 29 months after the first laparoscopy; endo stage: no change – improvement or worsening, but the majority did not have any change in the endometriosis stage which is surprising. They were operated on, they were on hormonal suppression and still the endometriosis stage was no different from the initial stage at the first laparoscopy. What is happening?
Also in this study, out of these 90 women, another 33 received a third laparoscopy because the pain came back after the second one, a median of 27 months after the second laparoscopy and again, endometriosis stayed more or less the same – no change, improvement or worsening. It is puzzling because it shows whatever we do it seems that there is a significant proportion of girls that cannot be helped properly with this approach.
Then postoperative norethindrone acetate as an adjuvant to surgery; there is a paper in press in the journal of Pediatric and Adolescent Gynecology showing that this can be useful for young women resistant to other medical treatments. This is again a retrospective case series about 200 women, median 19 years old. They all had minimum mild endometriosis. This is a selective group again retrospective of patients who got an operation and then were treated with only norethindrone acetate after the surgery. Why, because they had persistent pain or bleeding on medication they used before the operation, being oral contraceptives, GnRH or they had a contraindication for estradiol use. The result was significantly improved pain scores for all patients except those who received previously GnRH plus addback. There was also a significant improvement in bleeding scores but 45 percent significant side-effects: wide weight gain, acne, mood lability and vasomotor instability. Whatever we gave in terms of hormonal suppression we also need to be very much aware of these side-effects, which lead to reduced compliance. We need better drugs in other words because what we have is simply not good enough.
And finally, the paper by my colleague, Dr. Yeung. I think it is excellent work. It is the first prospective case series and he should be congratulated for that effort and we should follow that. It is a prospective case series of teenagers, 17 with 12 to 19 years of age and they all had laparoscopically and histologically confirmed endometriosis. He performed operative laparoscopy for pain suspicious for endometriosis and found mostly minimal and mild, and some cases with moderate endometriosis. Then he looked at the rate of recurrent, persistent endometriosis after this complete laparoscopic excision. Follow up with a median of 23 months and based on the information I read in the paper seven out of 17 received postoperative temporary hormonal suppression at their own initiative, but there was no sub-analysis of the group who did not _____ out of 17 who did not receive hormone suppression was not analyzed separately. It would be interesting to have the separate data analysis for that group. In any case, if you look at the whole cohort of 17 pre-post comparison showed improvement for dysmenorrhea, dyskesia, painful bladder and quality of life, and other pain end points, but not for chronic pelvic pain or dyspareunia. Out of these 17, 47 percent required repeat surgery for persistent or recurrent pain. At repeat surgery half of them had some filmy adhesions but no endometriosis was found, not microscopically, and also not in the _____ peritoneal areas that were resected at the repeat laparoscopy. They did not contain any endometriosis.
What does that mean? I think it means that this is a way to be followed. We need to document outcomes whatever we do in these girls. We need to do it as strictly structured as possible and this is why we need electronic files to follow these patients longitudinally lifetime essentially, as from the moment of their first diagnosis with standardized questionnaires, which are in development. We need to look at postoperative complications, at pain with VAS scores, which are done at every six months every year just as part of the follow up system, quality of life, re-intervention recurrence rates for future fertility outcome. We need to report all of this.
In conclusion, coming back to the four initial points I wanted to make: prevalence of endometriosis in adolescents with pelvic pain resistant to oral contraceptives or pain killers: 62 percent, one third with moderate to severe endometriosis. This means if we do a laparoscopy we have to be prepared that it may be more severe than minimum mild endometriosis. Second, prevalence of dysmenorrhea in adolescents: 42 percent; at 13, 40 percent, at 15 to 17 years - 52 percent and 18 to 19 years associated with reduced quality of life and resistant to COGs or NSAIDs in four to five percent, which is the target population we need to get in earlier.
Early detection: we need to validate the questionnaires. We need to use them then again in prospective research in primary health care professional environments, in school doctors to improve the timely referral to endometriosis centers of expertise.
And finally, can early treatment of endometriosis, of adolescent endometriosis prevent adult endometriosis? We do not know. We need to do the research. We need to start with well designed prospective cases, which everybody can do. It means that every patient who comes to you at the age of 13, 14 and 15 with laparoscopy confirmed endometriosis you follow her up. You can do a patient preference study whether you take or give her oral contraceptives or just spontaneous, it does not matter. But record it and publish it because that is the information we need. Once we have more information on that level then we can start prospective controlled cohort studies where we compare different managements. Ideally, of course, also in that population randomized controlled trials. In order to do so we need to agree on terms and definitions in adult endometriosis but also in adolescent endometriosis. We need to agree what is a complication, what is a recurrence? Many other things are so variable and subjective that everybody reports in a different way and as long as we do that we will not make any progress. One way how we can achieve this is working on the new ICD-11 diagnostic codes with WHO. I am involved in a working group there and I think if we can get global consensus on a number of terms and definitions in ICD-11, then worldwide we will report the same thing because one term will have the same definition everywhere.
I would like finally to thank my colleagues at the Leuven University Center of Reproductive Medicine and within which also the Leuven endometriosis research group is situated. I would like to thank you for your attention.
